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Clinical Pharmacokinetics and Pharmacodynamics of Tacrolimus in Solid Organ Transplantation

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Abstract

The aim of this review is to analyse critically the recent literature on the clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplant recipients.

Dosage and target concentration recommendations for tacrolimus vary from centre to centre, and large pharmacokinetic variability makes it difficult to predict what concentration will be achieved with a particular dose or dosage change. Therapeutic ranges have not been based on statistical approaches. The majority of pharmacokinetic studies have involved intense blood sampling in small homogeneous groups in the immediate post-transplant period. Most have used nonspecific immunoassays and provide little information on pharmacokinetic variability. Demographic investigations seeking correlations between pharmacokinetic parameters and patient factors have generally looked at one covariate at a time and have involved small patient numbers. Factors reported to influence the pharmacokinetics of tacrolimus include the patient group studied, hepatic dysfunction, hepatitis C status, time after transplantation, patient age, donor liver characteristics, recipient race, haematocrit and albumin concentrations, diurnal rhythm, food administration, corticosteroid dosage, diarrhoea and cytochrome P450 (CYP) isoenzyme and P-glycoprotein expression. Population analyses are adding to our understanding of the pharmacokinetics of tacrolimus, but such investigations are still in their infancy. A significant proportion of model variability remains unexplained. Population modelling and Bayesian forecasting may be improved if CYP isoenzymes and/or P-glycoprotein expression could be considered as covariates.

Reports have been conflicting as to whether low tacrolimus trough concentrations are related to rejection. Several studies have demonstrated a correlation between high trough concentrations and toxicity, particularly nephrotoxicity. The best predictor of pharmacological effect may be drug concentrations in the transplanted organ itself. Researchers have started to question current reliance on trough measurement during therapeutic drug monitoring, with instances of toxicity and rejection occurring when trough concentrations are within ‘acceptable’ ranges. The correlation between blood concentration and drug exposure can be improved by use of non-trough timepoints. However, controversy exists as to whether this will provide any great benefit, given the added complexity in monitoring. Investigators are now attempting to quantify the pharmacological effects of tacrolimus on immune cells through assays that measure in vivo calcineurin inhibition and markers of immunosuppression such as cytokine concentration. To date, no studies have correlated pharmacodynamic marker assay results with immunosuppressive efficacy, as determined by allograft outcome, or investigated the relationship between calcineurin inhibition and drug adverse effects. Little is known about the magnitude of the pharmacodynamic variability of tacrolimus.

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References

  1. Plosker GL, Foster RH. Tacrolimus: a further update of its pharmacology and therapeutic use in the management of organ transplantation. Drugs 2000; 59(2): 323–89

    Article  PubMed  CAS  Google Scholar 

  2. Pham SM, Kormos RL, Kawai A, et al. Tacrolimus (FK 506) in clinical cardiac transplantation: a five-year experience. Transplant Proc 1996; 28(2): 1002–4

    PubMed  CAS  Google Scholar 

  3. De Bonis M, Reynolds L, Barros J, et al. Tacrolimus as a rescue immunosuppressant after heart transplantation. Eur J Cardiothorac Surg 2001; 19(5): 690–5

    Article  PubMed  Google Scholar 

  4. Crespo-Leiro MG, Paniagua MJ, Mosquera I, et al. Replacement of cyclosporine by tacrolimus for immunosuppression in heart transplant patients: safety and efficacy. Transplant Proc 2002; 34(1): 113–4

    Article  PubMed  CAS  Google Scholar 

  5. Swenson JM, Fricker FJ, Armitage JM. Immunosuppression switch in pediatric heart transplant recipients: cyclosporine to FK 506. J Am Coll Cardiol 1995; 25(5): 1183–8

    Article  PubMed  CAS  Google Scholar 

  6. Reyes J, Mazariegos GV, Bond GM, et al. Pediatric intestinal transplantation: historical notes, principles and controversies. Pediatr Transplant 2002; 6(3): 193–207

    Article  PubMed  Google Scholar 

  7. Kato T, Ruiz P, Thompson JF, et al. Intestinal and multivisceral transplantation. World J Surg 2002; 26(2): 226–37

    Article  PubMed  Google Scholar 

  8. Jindal RM, Dubernard JM. Towards a specific immunosuppression for pancreas and islet grafts. Clin Transplant 2000; 14(3): 242–5

    Article  PubMed  CAS  Google Scholar 

  9. Stratta RJ. Optimal immunosuppression in pancreas transplantation. Transplant Proc 1999; 31 (1–2): 619–21

    Article  PubMed  CAS  Google Scholar 

  10. Stratta RJ, Taylor RJ, Castaldo P, et al. FK 506 induction and rescue therapy in pancreas transplant recipients. Transplant Proc 1996; 28(2): 991–2

    PubMed  CAS  Google Scholar 

  11. Gruessner RW. Tacrolimus in pancreas transplantation: a multicenter analysis. Tacrolimus Pancreas Transplant Study Group. Clin Transplant 1997; 11(4): 299–312

    PubMed  CAS  Google Scholar 

  12. Jordan ML, Shapiro R, Gritsch HA, et al. Long-term results of pancreas transplantation under tacrolimus immunosuppression. Transplantation 1999; 67(2): 266–72

    Article  PubMed  CAS  Google Scholar 

  13. Ratanatharathorn V, Nash RA, Przepiorka D, et al. Phase III study comparing methotrexate and tacrolimus (Prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood 1998; 92(7): 2303–14

    PubMed  CAS  Google Scholar 

  14. Fay JW, Wingard JR, Antin JH, et al. FK506 (tacrolimus) monotherapy for prevention of graft-versus-host disease after histocompatible sibling allogenic bone marrow transplantation. Blood 1996; 87(8): 3514–9

    PubMed  CAS  Google Scholar 

  15. Jacobson P, Uberti J, Davis W, et al. Tacrolimus: a new agent for the prevention of graft-versus-host disease in hematopoietic stem cell transplantation. Bone Marrow Transplant 1998; 22(3): 217–25

    Article  PubMed  CAS  Google Scholar 

  16. Lee TJ, Kennedy LA. Tacrolimus: an alternative for graft-versus-host disease prevention. Ann Pharmacother 2000; 34(3): 377–81

    Article  PubMed  CAS  Google Scholar 

  17. Yanik G, Levine JE, Ratanatharathorn V, et al. Tacrolimus (FK506) and methotrexate as prophylaxis for acute graft-versus-host disease in pediatric allogeneic stem cell transplantation. Bone Marrow Transplant 2000; 26(2): 161–7

    Article  PubMed  CAS  Google Scholar 

  18. Horning NR, Lynch JP, Sundaresan SR, et al. Tacrolimus therapy for persistent or recurrent acute rejection after lung transplantation. J Heart Lung Transplant 1998; 17(8): 761–7

    PubMed  CAS  Google Scholar 

  19. Kur F, Reichenspurner H, Meiser BM, et al. Tacrolimus (FK506) as primary immunosuppressant after lung transplantation. Thorac Cardiovasc Surg 1999; 47(3): 174–8

    Article  PubMed  CAS  Google Scholar 

  20. Lipson DA, Palevsky HI, Kotloff RM, et al. Conversion to tacrolimus (FK506) from cyclosporine after orthotopic lung transplantation. Transplant Proc 1998; 30(4): 1505–7

    Article  PubMed  CAS  Google Scholar 

  21. Reichenspurner H, Kur F, Treede H, et al. Optimization of the immunosuppressive protocol after lung transplantation. Transplantation 1999; 68(1): 67–71

    Article  PubMed  CAS  Google Scholar 

  22. Treede H, Klepetko W, Reichenspurner H, et al. Tacrolimus versus cyclosporine after lung transplantation: a prospective, open, randomized two-center trial comparing two different immunosuppressive protocols. J Heart Lung Transplant 2001; 20(5): 511–7

    Article  PubMed  CAS  Google Scholar 

  23. Busuttil RW, Holt CD. Tacrolimus is superior to cyclosporine in liver transplantation. Transplant Proc 1998; 30(5): 2174–8

    Article  PubMed  CAS  Google Scholar 

  24. Cao S, Cox KL, Berquist W, et al. Long-term outcomes in pediatric liver recipients: comparison between cyclosporin A and tacrolimus. Pediatr Transplant 1999; 3(1): 22–6

    Article  PubMed  CAS  Google Scholar 

  25. McDiarmid SV. The use of tacrolimus in pediatric liver transplantation. J Pediatr Gastroenterol Nutr 1998; 26(1): 90–102

    Article  PubMed  CAS  Google Scholar 

  26. Reyes J, Jain A, Mazariegos G, et al. Long-term results after conversion from cyclosporine to tacrolimus in pediatric liver transplantation for acute and chronic rejection. Transplantation 2000; 69(12): 2573–80

    Article  PubMed  CAS  Google Scholar 

  27. Berloco P, Rossi M, Pretagostini R, et al. Tacrolimus as cornerstone immunosuppressant in kidney transplantation. Transplant Proc 2001; 33(1–2): 994–6

    Article  PubMed  CAS  Google Scholar 

  28. Laskow DA, Neylan JF, Shapiro RS, et al. The role of tacrolimus in adult kidney transplantation: a review. Clin Transplant 1998; 12(6): 489–503

    PubMed  CAS  Google Scholar 

  29. Shapiro R. Tacrolimus in solid organ transplantation: an update. Transplant Proc 1999; 31(6): 2203–5

    Article  PubMed  CAS  Google Scholar 

  30. Shapiro R. Tacrolimus in pediatric renal transplantation: a review. Pediatr Transplant 1998; 2(4): 270–6

    PubMed  CAS  Google Scholar 

  31. Venkataramanan R, Swaminathan A, Prasad T, et al. Clinical pharmacokinetics of tacrolimus. Clin Pharmacokinet 1995; 29(6): 404–30

    Article  PubMed  CAS  Google Scholar 

  32. Trull AK. Therapeutic monitoring of tacrolimus. Ann Clin Biochem 1998; 35 (Pt 2): 167–80

    PubMed  CAS  Google Scholar 

  33. Taylor DO, Barr ML, Meiser BM, et al. Suggested guidelines for the use of tacrolimus in cardiac transplant recipients. J Heart Lung Transplant 2001; 20(7): 734–8

    Article  PubMed  CAS  Google Scholar 

  34. Walker S, Habib S, Rose M, et al. Clinical use and bioavailability of tacrolimus in heart-lung and double lung transplant recipients with cystic fibrosis. Transplant Proc 1998; 30(4): 1519–20

    Article  PubMed  CAS  Google Scholar 

  35. Tacrolimus (Prograf®): prescribing information. Deerfield (IL): Fujisawa Healthcare Inc., Aug 2003 [online]. Available from URL: http://www.fujisawa.com/medinfo/pi/pi_main_pg.htm [Accessed 2004 Jun 14]

  36. van Hooff JP, Boots JM, van Duijnhoven EM, et al. Dosing and management guidelines for tacrolimus in renal transplant patients. Transplant Proc 1999; 31(7A): 54–7S

    Article  Google Scholar 

  37. Busuttil RW, Klintmalm GB, Lake JR, et al. General guidelines for the use of tacrolimus in adult liver transplant patients. Transplantation 1996; 61(5): 845–7

    Article  PubMed  CAS  Google Scholar 

  38. Garrity ER, Hertz MI, Trulock EP, et al. Suggested guidelines for the use of tacrolimus in lung-transplant recipients. J Heart Lung Transplant 1999; 18(3): 175–6

    Article  PubMed  Google Scholar 

  39. Gruessner RW, Bartlett ST, Burke GW, et al. Suggested guidelines for the use of tacrolimus in pancreas/kidney transplantation. Clin Transplant 1998; 12(3): 260–2

    PubMed  CAS  Google Scholar 

  40. Ellis D. Clinical use of tacrolimus (FK-506) in infants and children with renal transplants. Pediatr Nephrol 1995; 9(4): 487–94

    Article  PubMed  CAS  Google Scholar 

  41. Esquivel CO, So SK, McDiarmid SV, et al. Suggested guidelines for the use of tacrolimus in pediatric liver transplant patients. Transplantation 1996; 61(5): 847–8

    Article  PubMed  CAS  Google Scholar 

  42. van Mourik ID, Kelly DA. Immunosuppressive drugs in paediatric liver transplantation. Paediatr Drugs 2001; 3(1): 43–60

    Article  PubMed  Google Scholar 

  43. Furlan V, Debray D, Fourre C, et al. Conversion from cyclosporin A to tacrolimus in pediatric liver transplantation. Pediatr Transplant 2000; 4(3): 207–10

    Article  PubMed  CAS  Google Scholar 

  44. Gaston RS. Maintenance immunosuppression in the renal transplant recipient: an overview. Am J Kidney Dis 2001; 38 (6 Suppl. 6): S25–35

    Article  PubMed  CAS  Google Scholar 

  45. Kokado Y, Takahara S, Kyo M, et al. Low-dose tacrolimus (FK506)-based immunosuppressive protocol in living donor renal transplantation. Transpl Int 1998; 11 Suppl. 1: S60–4

    PubMed  Google Scholar 

  46. Hasegawa A, Takahashi K, Ito K, et al. Optimal use of tacrolimus in living donor renal transplantation in children. Transplant Proc 2002; 34(5): 1939–41

    Article  PubMed  CAS  Google Scholar 

  47. Wallemacq PE, Furlan V, Moller A, et al. Pharmacokinetics of tacrolimus (FK506) in paediatric liver transplant recipients. Eur J Drug Metab Pharmacokinet 1998; 23(3): 367–70

    Article  PubMed  CAS  Google Scholar 

  48. Gruber SA, Hewitt JM, Sorenson AL, et al. Pharmacokinetics of FK506 after intravenous and oral administration in patients awaiting renal transplantation. J Clin Pharmacol 1994; 34(8): 859–64

    PubMed  CAS  Google Scholar 

  49. Jain A, Venkataramanan R, Todo S, et al. Intravenous, oral pharmacokinetics, and oral dosing of FK 506 in small bowel transplant patients. Transplant Proc 1992; 24(3): 1181–2

    PubMed  CAS  Google Scholar 

  50. Fitzsimmons WE, Bekersky I, Dressler D, et al. Demographic considerations in tacrolimus pharmacokinetics. Transplant Proc 1998; 30(4): 1359–64

    Article  PubMed  CAS  Google Scholar 

  51. Neylan JF. Racial differences in renal transplantation after immunosuppression with tacrolimus versus cyclosporine. FK506 Kidney Transplant Study Group. Transplantation 1998; 65(4): 515–23

    Article  PubMed  CAS  Google Scholar 

  52. Neylan JF. Effect of race and immunosuppression in renal transplantation: three-year survival results from a US multicenter, randomized trial. FK506 Kidney Transplant Study Group. Transplant Proc 1998; 30(4): 1355–8

    Article  PubMed  CAS  Google Scholar 

  53. Mancinelli LM, Frassetto L, Floren LC, et al. The pharmacokinetics and metabolic disposition of tacrolimus: a comparison across ethnic groups. Clin Pharmacol Ther 2001; 69(1): 24–31

    Article  PubMed  CAS  Google Scholar 

  54. Felipe CR, Garcia C, Moreira S, et al. Choosing the right dose of new immunosuppressive drugs for new populations: importance of pharmacokinetic studies. Transplant Proc 2001; 33(1–2): 1095–6

    Article  PubMed  CAS  Google Scholar 

  55. van Duijnhoven E, Christiaans M, Schafer A, et al. Tacrolimus dosing requirements in diabetic and nondiabetic patients calculated from pretransplantation data. Transplant Proc 1998; 30(4): 1266–7

    Article  PubMed  Google Scholar 

  56. Hu RH, Lee PH, Tsai MK. Clinical influencing factors for daily dose, trough level, and relative clearance of tacrolimus in renal transplant recipients. Transplant Proc 2000; 32(7): 1689–92

    Article  PubMed  CAS  Google Scholar 

  57. Mekki Q, Lee CC, Carrier S, et al. The effect of food on oral bioavailability of tacrolimus (FK506) in liver transplant patients [abstract]. Clin Pharmacol Ther 1993; 53(2): 229

    Google Scholar 

  58. Bekersky I, Dressler D, Mekki QA. Effect of low- and high-fat meals on tacrolimus absorption following 5mg single oral doses to healthy human subjects. J Clin Pharmacol 2001; 41(2): 176–82

    Article  PubMed  CAS  Google Scholar 

  59. Bekersky I, Dressler D, Mekki Q. Effect of time of meal consumption on bioavailability of a single oral 5mg tacrolimus dose. J Clin Pharmacol 2001; 41(3): 289–97

    Article  PubMed  CAS  Google Scholar 

  60. Venkataramanan R, Jain A, Warty VS, et al. Pharmacokinetics of FK 506 in transplant patients. Transplant Proc 1991; 23(6): 2736–40

    PubMed  CAS  Google Scholar 

  61. Jusko WJ, Piekoszewski W, Klintmalm GB, et al. Pharmacokinetics of tacrolimus in liver transplant patients. Clin Pharmacol Ther 1995; 57(3): 281–90

    Article  PubMed  CAS  Google Scholar 

  62. Tuteja S, Alloway RR, Johnson JA, et al. The effect of gut metabolism on tacrolimus bioavailability in renal transplant recipients. Transplantation 2001; 71(9): 1303–7

    Article  PubMed  CAS  Google Scholar 

  63. Benet LZ. Impact of intraindividual variability of drugs on therapeutic outcomes: lessons from outside transplantation. Transplant Proc 1998; 30(5): 1650–1

    Article  PubMed  CAS  Google Scholar 

  64. Zhang Y, Benet LZ. The gut as a barrier to drug absorption: combined role of cytochrome P450 3A and P-glycoprotein. Clin Pharmacokinet 2001; 40(3): 159–68

    Article  PubMed  CAS  Google Scholar 

  65. Lampen A, Christians U, Guengerich FP, et al. Metabolism of the immunosuppressant tacrolimus in the small intestine: cytochrome P450, drug interactions, and interindividual variability. Drug Metab Dispos 1995; 23(12): 1315–24

    PubMed  CAS  Google Scholar 

  66. Lampen A, Christians U, Gonschior AK, et al. Metabolism of the macrolide immunosuppressant, tacrolimus, by the pig gut mucosa in the Ussing chamber. Br J Pharmacol 1996; 117(8): 1730–4

    Article  PubMed  CAS  Google Scholar 

  67. Paine MF, Khalighi M, Fisher JM, et al. Characterization of interintestinal and intraintestinal variations in human CYP3A-dependent metabolism. J Pharmacol Exp Ther 1997; 283(3): 1552–62

    PubMed  CAS  Google Scholar 

  68. Wacher VJ, Silverman JA, Zhang Y, et al. Role of P-glycoprotein and cytochrome P450 3A in limiting oral absorption of peptides and peptidomimetics. J Pharm Sci 1998; 87(11): 1322–30

    Article  PubMed  CAS  Google Scholar 

  69. de Waziers I, Cugnenc PH, Yang CS, et al. Cytochrome P 450 isoenzymes, epoxide hydrolase and glutathione transferases in rat and human hepatic and extrahepatic tissues. J Pharmacol Exp Ther 1990; 253(1): 387–94

    PubMed  Google Scholar 

  70. Benet LZ, Izumi T, Zhang Y, et al. Intestinal MDR transport proteins and P-450 enzymes as barriers to oral drug delivery. J Control Release 1999; 62(1-2): 25–31

    Article  PubMed  CAS  Google Scholar 

  71. Gan LS, Moseley MA, Khosla B, et al. CYP3A-like cytochrome P450-mediated metabolism and polarized efflux of cyclosporin A in Caco-2 cells. Drug Metab Dispos 1996; 24(3): 344–9

    PubMed  CAS  Google Scholar 

  72. Lo A, Burckart G. P-glycoprotein and drug therapy in organ transplantation. J Clin Pharmacol 1999; 39: 995–1005

    Article  PubMed  CAS  Google Scholar 

  73. Fojo AT, Ueda K, Slamon DJ, et al. Expression of a multidrug-resistance gene in human tumors and tissues. Proc Natl Acad Sci U S A 1987; 84(1): 265–9

    Article  PubMed  CAS  Google Scholar 

  74. Lown KS, Mayo RR, Leichtman AB, et al. Role of intestinal P-glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine. Clin Pharmacol Ther 1997; 62(3): 248–60

    Article  PubMed  CAS  Google Scholar 

  75. Venkataramanan R, Jain A, Warty VW, et al. Pharmacokinetics of FK 506 following oral administration: a comparison of FK 506 and cyclosporine. Transplant Proc 1991; 23(1 Pt 2): 931–3

    PubMed  CAS  Google Scholar 

  76. Jain AB, Venkataramanan R, Cadoff E, et al. Effect of hepatic dysfunction and T tube clamping on FK 506 pharmacokinetics and trough concentrations. Transplant Proc 1990; 22(1): 57–9

    PubMed  CAS  Google Scholar 

  77. Bottiger Y, Undre N, Sawe J, et al. Effect of bile flow on the absorption of tacrolimus in liver allograft transplantation. Transplant Proc 2002; 34(5): 1544–5

    Article  PubMed  CAS  Google Scholar 

  78. Murray M, Grogan TA, Lever J, et al. Comparison of tacrolimus absorption in transplant patients receiving continuous versus interrupted enteral nutritional feeding. Ann Pharmacother 1998; 32(6): 633–6

    Article  PubMed  CAS  Google Scholar 

  79. Warty VS, Venkataramanan R, Zendehrouh P, et al. Practical aspects of FK 506 analysis (Pittsburgh experience). Transplant Proc 1991; 23(6): 2730–1

    PubMed  CAS  Google Scholar 

  80. Jusko WJ, D’Ambrosio R. Monitoring FK 506 concentrations in plasma and whole blood. Transplant Proc 1991; 23(6): 2732–5

    PubMed  CAS  Google Scholar 

  81. Beysens AJ, Wijnen RM, Beuman GH, et al. FK 506: monitoring in plasma or in whole blood? Transplant Proc 1991; 23(6): 2745–7

    PubMed  CAS  Google Scholar 

  82. Jusko WJ. Analysis of tacrolimus (FK 506) in relation to therapeutic drug monitoring. Ther Drug Monit 1995; 17(6): 596–601

    Article  PubMed  CAS  Google Scholar 

  83. Ericzon BG, Ekqvist B, Groth CG, et al. Pharmacokinetics of FK 506 during maintenance therapy in liver transplant patients. Transplant Proc 1991; 23(6): 2775–6

    PubMed  CAS  Google Scholar 

  84. Machida M, Takahara S, Ishibashi M, et al. Effect of temperature and hematocrit on plasma concentration of FK 506. Transplant Proc 1991; 23(6): 2753–4

    PubMed  CAS  Google Scholar 

  85. Nagase K, Iwasaki K, Nozaki K, et al. Distribution and protein binding of FK506, a potent immunosuppressive macrolide lactone, in human blood and its uptake by erythrocytes. J Pharm Pharmacol 1994; 46(2): 113–7

    Article  PubMed  CAS  Google Scholar 

  86. Kay JE, Sampare-Kwateng E, Geraghty F, et al. Uptake of FK 506 by lymphocytes and erythrocytes. Transplant Proc 1991; 23(6): 2760–2

    PubMed  CAS  Google Scholar 

  87. Kobayashi M, Tamura K, Katayama N, et al. FK 506 assay past and present-characteristics of FK 506 ELISA. Transplant Proc 1991; 23(6): 2725–9

    PubMed  CAS  Google Scholar 

  88. Piekoszewski W, Chow FS, Jusko WJ. Disposition of tacrolimus (FK 506) in rabbits: role of red blood cell binding in hepatic clearance. Drug Metab Dispos 1993; 21(4): 690–8

    PubMed  CAS  Google Scholar 

  89. Jain A, Venkataramanan R, Lever J, et al. FK506 and pregnancy in liver transplant patients. Transplantation 1993; 56(6): 1588–9

    PubMed  CAS  Google Scholar 

  90. Jain A, Venkataramanan R, Fung JJ, et al. Pregnancy after liver transplantation under tacrolimus. Transplantation 1997; 64(4): 559–65

    Article  PubMed  CAS  Google Scholar 

  91. Jain AB, Fung JJ, Tzakis AG, et al. Comparative study of cyclosporine and FK 506 dosage requirements in adult and pediatric orthotopic liver transplant patients. Transplant Proc 1991; 23(6): 2763–6

    PubMed  CAS  Google Scholar 

  92. Wallemacq PE, Verbeeck RK. Comparative clinical pharmacokinetics of tacrolimus in paediatric and adult patients. Clin Pharmacokinet 2001; 40(4): 283–95

    Article  PubMed  CAS  Google Scholar 

  93. Moller A, Iwasaki K, Kawamura A, et al. The disposition of 14C-labeled tacrolimus after intravenous and oral administration in healthy human subjects. Drug Metab Dispos 1999; 27(6): 633–6

    PubMed  CAS  Google Scholar 

  94. Wrighton SA, VandenBranden M, Ring BJ. The human drug metabolizing cytochromes P450. J Pharmacokinet Biopharm 1996; 24(5): 461–73

    PubMed  CAS  Google Scholar 

  95. de Wildt SN, Kearns GL, Leeder JS, et al. Cytochrome P450 3A: ontogeny and drug disposition. Clin Pharmacokinet 1999; 37(6): 485–505

    Article  PubMed  Google Scholar 

  96. Karanam BV, Vincent SH, Newton DJ, et al. FK 506 metabolism in human liver microsomes: investigation of the involvement of cytochrome P450 isozymes other than CYP3A4. Drug Metab Dispos 1994; 22(5): 811–4

    PubMed  CAS  Google Scholar 

  97. Lemoine A, Azoulay D, Gries JM, et al. Relationship between graft cytochrome P-450 3A content and early morbidity after liver transplantation. Transplantation 1993; 56(6): 1410–4

    Article  PubMed  CAS  Google Scholar 

  98. Sattler M, Guengerich FP, Yun CH, et al. Cytochrome P-450 3A enzymes are responsible for biotransformation of FK506 and rapamycin in man and rat. Drug Metab Dispos 1992; 20(5): 753–61

    PubMed  CAS  Google Scholar 

  99. Wilkinson GR. Cytochrome P4503A (CYP3A) metabolism: prediction of in vivo activity in humans. J Pharmacokinet Biopharm 1996; 24(5): 475–90

    PubMed  CAS  Google Scholar 

  100. Gellner KR, Eiselt R, Hustert E, et al. Genomic organization of the human CYP3A locus: identification of a new, inducible CYP3A gene. Pharmacogenetics 2001; 11(2): 111–21

    Article  PubMed  CAS  Google Scholar 

  101. Lamba JK, Lin YS, Schuetz EG, et al. Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev 2002; 54(10): 1271–94

    Article  PubMed  CAS  Google Scholar 

  102. Wrighton SA, Brian WR, Sari MA, et al. Studies on the expression and metabolic capabilities of human liver cytochrome P450IIIA5 (HLp3). Mol Pharmacol 1990; 38(2): 207–13

    PubMed  CAS  Google Scholar 

  103. Schuetz JD, Molowa DT, Guzelian PS. Characterization of a cDNA encoding a new member of the glucocorticoid-responsive cytochromes P450 in human liver. Arch Biochem Biophys 1989; 274(2): 355–65

    Article  PubMed  CAS  Google Scholar 

  104. Tateishi T, Watanabe M, Moriya H, et al. No ethnic difference between Caucasian and Japanese hepatic samples in the expression frequency of CYP3A5 and CYP3A7 proteins. Biochem Pharmacol 1999; 57(8): 935–9

    Article  PubMed  CAS  Google Scholar 

  105. Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 2001; 27(4): 383–91

    Article  PubMed  CAS  Google Scholar 

  106. Lin YS, Dowling AL, Quigley SD, et al. Co-regulation of CYP3A4 and CYP3A5 and contribution to hepatic and intestinal midazolam metabolism. Mol Pharmacol 2002; 62(1): 162–72

    Article  PubMed  CAS  Google Scholar 

  107. Domanski TL, Finta C, Halpert JR, et al. cDNA cloning and initial characterization of CYP3A43, a novel human cytochrome P450. Mol Pharmacol 2001; 59(2): 386–92

    PubMed  CAS  Google Scholar 

  108. Westlind A, Malmebo S, Johansson I, et al. Cloning and tissue distribution of a novel human cytochrome p450 of the CYP3A subfamily, CYP3A43. Biochem Biophys Res Commun 2001; 281(5): 1349–55

    Article  PubMed  CAS  Google Scholar 

  109. Christians U, Braun F, Kosian N, et al. High performance liquid chromatography/mass spectrometry of FK 506 and its metabolites in blood, bile, and urine of liver grafted patients. Transplant Proc 1991; 23(6): 2741–4

    PubMed  CAS  Google Scholar 

  110. Christians U, Kruse C, Kownatzki R, et al. Measurement of FK 506 by HPLC and isolation and characterization of its metabolites. Transplant Proc 1991; 23(1 Pt 2): 940–1

    PubMed  CAS  Google Scholar 

  111. Christians U, Radeke HH, Kownatzki R, et al. Isolation of an immunosuppressive metabolite of FK506 generated by human microsome preparations. Clin Biochem 1991; 24(3): 271–5

    Article  PubMed  CAS  Google Scholar 

  112. Christians U, Braun F, Schmidt M, et al. Specific and sensitive measurement of FK506 and its metabolites in blood and urine of liver-graft recipients. Clin Chem 1992; 38(10): 2025–32

    PubMed  CAS  Google Scholar 

  113. Iwasaki K, Shiraga T, Matsuda H, et al. Further metabolism of FK506 (tacrolimus): identification and biological activities of the metabolites oxidized at multiple sites of FK506. Drug Metab Dispos 1995; 23(1): 28–34

    PubMed  CAS  Google Scholar 

  114. Alak AM, Moy S. Biological activity of tacrolimus (FK506) and its metabolites from whole blood of kidney transplant patients. Transplant Proc 1997; 29(5): 2487–90

    Article  PubMed  CAS  Google Scholar 

  115. Gonschior AK, Christians U, Winkler M, et al. Tacrolimus (FK506) metabolite patterns in blood from liver and kidney transplant patients. Clin Chem 1996; 42(9): 1426–32

    PubMed  CAS  Google Scholar 

  116. Venkataramanan R, Jain AK, Lever J, et al. Pharmacokinetics of tacrolimus (Tac) in transplant patients [abstract]. Ther Drug Monit 1995; 17(4): 416

    Article  Google Scholar 

  117. Gonschior AK, Christians U, Braun F, et al. Measurement of blood concentrations of FK506 (tacrolimus) and its metabolites in seven liver graft patients after the first dose by h.p.l.c.-MS and microparticle enzyme immunoassay (MEIA). Br J Clin Pharmacol 1994; 38(6): 567–71

    Article  PubMed  CAS  Google Scholar 

  118. Iwasaki K, Shiraga T, Nagase K, et al. Isolation, identification, and biological activities of oxidative metabolites of FK506, a potent immunosuppressive macrolide lactone. Drug Metab Dispos 1993; 21(6): 971–7

    PubMed  CAS  Google Scholar 

  119. Boswell GW, Bekersky I, Fay J, et al. Tacrolimus pharmacokinetics in BMT patients. Bone Marrow Transplant 1998; 21(1): 23–8

    Article  PubMed  CAS  Google Scholar 

  120. Mekki QA, Piscitelli D, Fitzsimmons WE. Pharmacokinetics of tacrolimus in bone marrow transplant patients [abstract]. Clin Pharmacol Ther 1993; 55(2): 149

    Google Scholar 

  121. Bekersky I, Dressler D, Alak A, et al. Comparative tacrolimus pharmacokinetics: normal versus mildly hepatically impaired subjects. J Clin Pharmacol 2001; 41(6): 628–35

    Article  PubMed  CAS  Google Scholar 

  122. Hebert MF, Fisher RM, Marsh CL, et al. Effects of rifampin on tacrolimus pharmacokinetics in healthy volunteers. J Clin Pharmacol 1999; 39(1): 91–6

    Article  PubMed  CAS  Google Scholar 

  123. Steinmuller DR. FK506 and organ transplantation. Austin (TX): Medical Intelligence Unit, RG Landers Co, 1994: 1–111

    Google Scholar 

  124. Venkataramanan R, Jain A, Lever J, et al. High dose tacrolimus requirements in transplant patients [abstract]. Pharm Res 1994; 7: 329–33

    Google Scholar 

  125. Satoh S, Tada H, Tachiki Y, et al. Chrono and clinical pharmacokinetic study of tacrolimus in continuous intravenous administration. Int J Urol 2001; 8(7): 353–8

    Article  PubMed  CAS  Google Scholar 

  126. Aweeka FT, Benet LZ, Gambertoglio JG, et al. Comparitive pharmacokinetics of orally (PO) and intravenously (IV) administered tacrolimus (FK506) in pre- and post-kidney transplant recipients [abstract]. Clin Pharmacol Ther 1993; 53(2): 151

    Google Scholar 

  127. Lee CC, Hewitt JM, Aweeka FT, et al. Pharmacokinetics of tacrolimus (FK506) prior to kidney transplantation [abstract]. Clin Pharmacol Ther 1993; 53(2): 238

    Google Scholar 

  128. Saito K, Suwa M, Nakagawa Y, et al. Study of pharmacokinetic parameters of tacrolimus by different oral administration periods in renal transplantation. Transplant Proc 2002; 34(5): 1726–9

    Article  PubMed  CAS  Google Scholar 

  129. Mekki QA, Lee CC, Aweeka FT, et al. Pharmacokinetics of tacrolimus (FK506) in kidney transplant patients [abstract]. Clin Pharmacol Ther 1993; 53(2): 238

    Google Scholar 

  130. Tuteja S, Alloway RR, Johnson JA, et al. The effect of gut metabolism on tacrolimus bioavailability in renal transplant recipients. Transplantation 2001; 71(9): 1303–7

    Article  PubMed  CAS  Google Scholar 

  131. Lee CC, Jusko WJ, Shaefer MS, et al. Pharmacokinetics of tacrolimus (FK506) in liver transplant patients [abstract]. Clin Pharmacol Ther 1993; 53(2): 181

    Google Scholar 

  132. Jain A, Venkataramanan R, Lever J, et al. FK 506 in small bowel transplant recipients: pharmacokinetics and dosing. Transplant Proc 1994; 26(3): 1609–10

    PubMed  CAS  Google Scholar 

  133. Venkataramanan R, Jain A, Cadoff E, et al. Pharmacokinetics of FK 506: preclinical and clinical studies. Transplant Proc 1990; 22(1): 52–6

    PubMed  CAS  Google Scholar 

  134. Shishido S, Asanuma H, Tajima E, et al. Pharmacokinetics of tacrolimus in pediatric renal transplant recipients. Transplant Proc 2001; 33(1–2): 1066–8

    Article  PubMed  CAS  Google Scholar 

  135. Webb N, Stevenson P, Lewis M, et al. Pharmacokinetics of tacrolimus in paediatric renal transplant recipients. Transplant Proc 2002; 34(5): 1948–50

    Article  PubMed  CAS  Google Scholar 

  136. Sewing KF. Pharmacokinetics, dosing principles, and blood level monitoring of FK506. Transplant Proc 1994; 26(6): 3267–9

    PubMed  CAS  Google Scholar 

  137. Regazzi MB, Rinaldi M, Molinaro M, et al. Clinical pharmacokinetics of tacrolimus in heart transplant recipients. Ther Drug Monit 1999; 21(1): 2–7

    Article  PubMed  CAS  Google Scholar 

  138. Molinaro M, Regazzi MB, Pasquino S, et al. Pharmacokinetics of tacrolimus during the early phase after heart transplantation. Transplant Proc 2001; 33(3): 2386–9

    Article  PubMed  CAS  Google Scholar 

  139. Undre N, Stevenson P. Pharmacokinetics of tacrolimus in heart transplantation. Transplant Proc 2002; 34(5): 1836–8

    Article  PubMed  CAS  Google Scholar 

  140. Mehta P, Beltz S, Kedar A, et al. Increased clearance of tacrolimus in children: need for higher doses and earlier initiation prior to bone marrow transplantation. Bone Marrow Transplant 1999; 24(12): 1323–7

    Article  PubMed  CAS  Google Scholar 

  141. Jusko WJ, Thomson AW, Fung J, et al. Consensus document: therapeutic monitoring of tacrolimus (FK-506). Ther Drug Monit 1995; 17(6): 606–14

    Article  PubMed  CAS  Google Scholar 

  142. Kuzuya T, Ogura Y, Motegi Y, et al. Interference of hematocrit in the tacrolimus II microparticle enzyme immunoassay. Ther Drug Monit 2002; 24(4): 507–11

    Article  PubMed  CAS  Google Scholar 

  143. McMasters P, Mirza DF, Ismail T, et al. Therapeutic drug monitoring of tacrolimus in clinical transplantation. Ther Drug Monit 1995; 17(6): 602–5

    Article  Google Scholar 

  144. Christians U, Jacobsen W, Benet LZ, et al. Mechanisms of clinically relevant drug interactions associated with tacrolimus. Clin Pharmacokinet 2002; 41(11): 813–51

    Article  PubMed  CAS  Google Scholar 

  145. Jain AB, Abu-Elmagd K, Abdallah H, et al. Pharmacokinetics of FK506 in liver transplant recipients after continuous intravenous infusion. J Clin Pharmacol 1993; 33(7): 606–11

    PubMed  CAS  Google Scholar 

  146. Abu-Elmagd K, Fung JJ, Alessiani M, et al. The effect of graft function on FK506 plasma levels, dosages, and renal function, with particular reference to the liver. Transplantation 1991; 52(1): 71–7

    Article  PubMed  CAS  Google Scholar 

  147. Abu-Elmagd KM, Fung JJ, Alessiani M, et al. Strategy of FK 506 therapy in liver transplant patients: effect of graft function. Transplant Proc 1991; 23(6): 2771–4

    PubMed  CAS  Google Scholar 

  148. Pou L, Brunet M, Andres I, et al. Influence of posttransplant time on dose and concentration of tacrolimus in liver transplant patients. Transpl Int 1998; 11 Suppl. 1: S270–1

    PubMed  Google Scholar 

  149. Manzanares C, Moreno M, Castellanos F, et al. Influence of hepatitis C virus infection on FK 506 blood levels in renal transplant patients. Transplant Proc 1998; 30(4): 1264–5

    Article  PubMed  CAS  Google Scholar 

  150. van den Berg AP, Haagsma EB, Gouw AS, et al. Recurrent HCV infection reduces the requirement for tacrolimus after liver transplantation. Transplant Proc 2001; 33(1–2): 1467

    Article  PubMed  Google Scholar 

  151. Moreno M, Manzanares C, Castellano F, et al. Monitoring of tacrolimus as rescue therapy in pediatric liver transplantation. Ther Drug Monit 1998; 20(4): 376–9

    Article  PubMed  CAS  Google Scholar 

  152. Horina JH, Wirnsberger GH, Kenner L, et al. Increased susceptibility for CsA-induced hepatotoxicity in kidney graft recipients with chronic viral hepatitis C. Transplantation 1993; 56(5): 1091–4

    Article  PubMed  CAS  Google Scholar 

  153. Undre NA, Schafer A. Factors affecting the pharmacokinetics of tacrolimus in the first year after renal transplantation. European Tacrolimus Multicentre Renal Study Group. Transplant Proc 1998; 30(4): 1261–3

    Article  PubMed  CAS  Google Scholar 

  154. Christiaans M, van Duijnhoven E, Beysens T, et al. Effect of breakfast on the oral bioavailability of tacrolimus and changes in pharmacokinetics at different times posttransplant in renal transplant recipients. Transplant Proc 1998; 30(4): 1271–3

    Article  PubMed  CAS  Google Scholar 

  155. McDiarmid SV, Colonna JO, Shaked A, et al. Differences in oral FK506 dose requirements between adult and pediatric liver transplant patients. Transplantation 1993; 55(6): 1328–32

    Article  PubMed  CAS  Google Scholar 

  156. Satomura K, Ozaki N, Okajima H, et al. Pharmacokinetics of FK 506 in living-related liver transplantation. Transplant Proc 1996; 28(2): 1005

    PubMed  CAS  Google Scholar 

  157. Yasuhara M, Hashida T, Toraguchi M, et al. Pharmacokinetics and pharmacodynamics of FK 506 in pediatric patients receiving living-related donor liver transplantations. Transplant Proc 1995; 27(1): 1108–10

    PubMed  CAS  Google Scholar 

  158. Uemoto S, Tanaka K, Honda K, et al. Experience with FK506 in living-related liver transplantation. Transplantation 1993; 55(2): 288–92

    Article  PubMed  CAS  Google Scholar 

  159. Cacciarelli TV, Esquivel CO, Cox KL, et al. Oral tacrolimus (FK506) induction therapy in pediatric orthotopic liver transplantation. Transplantation 1996; 61(8): 1188–92

    Article  PubMed  CAS  Google Scholar 

  160. MacFarlane GD, Venkataramanan R, McDiarmid SV, et al. Therapeutic drug monitoring of tacrolimus in pediatric liver transplant patients. Pediatr Transplant 2001; 5(2): 119–24

    Article  PubMed  CAS  Google Scholar 

  161. Przepiorka D, Blamble D, Hilsenbeck S, et al. Tacrolimus clearance is age-dependent within the pediatric population. Bone Marrow Transplant 2000; 26(6): 601–5

    Article  PubMed  CAS  Google Scholar 

  162. Mittal N, Thompson JF, Kato T, et al. Tacrolimus and diarrhea: pathogenesis of altered metabolism. Pediatr Transplant 2001; 5(2): 75–9

    Article  PubMed  CAS  Google Scholar 

  163. Teperman LW, Morgan GR, Diflo T, et al. Tacrolimus dose is donor age dependent [abstract]. 24th Annual Scientific Meeting of the American Society of Transplant Surgeons; 1998 May 13–15; Chicago

    Google Scholar 

  164. Taber DJ, Dupuis RE, Fann AL, et al. Tacrolimus dosing requirements and concentrations in adult living donor liver transplant recipients. Liver Transpl 2002; 8(3): 219–23

    Article  PubMed  Google Scholar 

  165. Trotter JF, Stolpman N, Wachs M, et al. Living donor liver transplant recipients achieve relatively higher immuno-suppressant blood levels than cadaveric recipients. Liver Transpl 2002; 8(3): 212–8

    Article  PubMed  Google Scholar 

  166. Troisi R, Militerno G, Hoste E, et al. Are reduced tacrolimus dosages needed in the early postoperative period following living donor liver transplantation in adults? Transplant Proc 2002; 34(5): 1531–2

    Article  PubMed  CAS  Google Scholar 

  167. Harihara Y, Sano K, Makuuchi M, et al. Correlation between graft size and necessary tacrolimus dose after living-related liver transplantation. Transplant Proc 2000; 32(7): 2166–7

    Article  PubMed  CAS  Google Scholar 

  168. Sugawara Y, Makuuchi M, Kaneko J, et al. Correlation between optimal tacrolimus doses and the graft weight in living donor liver transplantation. Clin Transplant 2002; 16(2): 102–6

    Article  PubMed  CAS  Google Scholar 

  169. Nakazawa Y, Chisuwa H, Ikegami T, et al. Relationship between in vivo FK506 clearance and in vitro 13-demethylation activity in living-related liver transplantation. Transplantation 1998; 66(8): 1089–93

    Article  PubMed  CAS  Google Scholar 

  170. Felipe CR, Silva HT, Machado PG, et al. The impact of ethnic miscegenation on tacrolimus clinical pharmacokinetics and therapeutic drug monitoring. Clin Transplant 2002; 16(4): 262–72

    Article  PubMed  Google Scholar 

  171. Uber PA, Mehra MR, Scott RL, et al. Ethnic disparities in the pharmacologic characteristics of tacrolimus in heart transplantation. Transplant Proc 2001; 33(1–2): 1581–2

    Article  PubMed  CAS  Google Scholar 

  172. Huang ML, Venkataramanan R, Burckart GJ, et al. Drug-binding proteins in liver transplant patients. J Clin Pharmacol 1988; 28(6): 505–6

    PubMed  CAS  Google Scholar 

  173. Min DI, Chen HY, Fabrega A, et al. Circadian variation of tacrolimus disposition in liver allograft recipients. Transplantation 1996; 62(8): 1190–2

    Article  PubMed  CAS  Google Scholar 

  174. Kimikawa M, Kamoya K, Toma H, et al. Effective oral administration of tacrolimus in renal transplant recipients. Clin Transplant 2001; 15(5): 324–9

    Article  PubMed  CAS  Google Scholar 

  175. van Duijnhoven E, Christiaans M, Boots J, et al. Evidence that fasting does not significantly affect trough levels of tacrolimus in stable renal transplant recipients. Transplant Proc 2002; 34(5): 1723–5

    Article  PubMed  Google Scholar 

  176. Eades SK, Boineau FG, Christensen ML. Increased tacrolimus levels in a pediatric renal transplant patient attributed to chronic diarrhea. Pediatr Transplant 2000; 4(1): 63–6

    Article  PubMed  CAS  Google Scholar 

  177. Hochleitner BW, Bosmuller C, Nehoda H, et al. Increased tacrolimus levels during diarrhea. Transpl Int 2001; 14(4): 230–3

    Article  PubMed  CAS  Google Scholar 

  178. Matsui A, Arakawa Y, Momoya T, et al. Apparently increased trough levels of tacrolimus caused by acute infantile diarrhea in two infants with biliary atresia after liver transplantation. Acta Paediatr Jpn 1996; 38(6): 699–701

    Article  PubMed  CAS  Google Scholar 

  179. Fruhwirth M, Fischer H, Simma B, et al. Rotavirus infection as cause of tacrolimus elevation in solid-organ- transplanted children. Pediatr Transplant 2001; 5(2): 88–92

    Article  PubMed  CAS  Google Scholar 

  180. Fruhwirth M, Fischer H, Simma B, et al. Elevated tacrolimus trough levels in association with mycophenolate mofetil-induced diarrhea: a case report. Pediatr Transplant 2001; 5(2): 132–4

    Article  PubMed  CAS  Google Scholar 

  181. Zylber-Katz E, Granot E. Abrupt increase of tacrolimus blood levels during an episode of Shigella infection in a child after liver transplantation. Ther Drug Monit 2001; 23(6): 647–9

    Article  PubMed  CAS  Google Scholar 

  182. Itagaki F, Hori T, Tomita T, et al. Effect of ascites on tacrolimus disposition in a liver transplant recipient. Ther Drug Monit 2001; 23(6): 644–6

    Article  PubMed  CAS  Google Scholar 

  183. Novelli M, Muiesan P, Mieli-Vergani G, et al. Oral absorption of tacrolimus in children with intestinal failure due to short or absent small bowel. Transpl Int 1999; 12(6): 463–5

    Article  PubMed  CAS  Google Scholar 

  184. Hasegawa T, Nara K, Kimura T, et al. Oral administration of tacrolimus in the presence of jejunostomy after liver transplantation. Pediatr Transplant 2001; 5(3): 204–9

    Article  PubMed  CAS  Google Scholar 

  185. Zheng H, Webber S, Zeevi A, et al. Tacrolimus dosing in pediatric heart transplant patients is related to CYP3A5 and MDR1 gene polymorphisms. Am J Transplant 2003; 3(4): 477–83

    Article  PubMed  CAS  Google Scholar 

  186. MacPhee IA, Fredericks S, Tai T, et al. The influence of pharmacogenetics on the time to achieve target tacrolimus concentrations after kidney transplantation. Am J Transplant 2004; 4(6): 914–9

    Article  PubMed  CAS  Google Scholar 

  187. McPhee IA, Fredericks S, Tai T, et al. Tacrolimus pharmacogenetics: polymorphisms associated with expression of cytochrome P4503A5 and P-glycoprotein correlate with dose requirement. Transplantation 2002; 74(11): 1486–9

    Article  Google Scholar 

  188. Hesselink DA, van Schaik RHN, van der Heiden IP, et al. Genetic polymorphisms of the CYP3A4, CYP3A5 and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors and cyclosporine and tacrolimus. Clin Pharmacol Ther 2003; 74(3): 245–54

    Article  PubMed  CAS  Google Scholar 

  189. de Wildt SN, Kearns GL, Leeder JS, et al. Cytochrome P4503A: ontogeny and drug disposition. Clin Pharmacokinet 1999; 37(6): 485–505

    Article  PubMed  Google Scholar 

  190. Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 2001; 27(4): 383–91

    Article  PubMed  CAS  Google Scholar 

  191. Hustert E, Haberl M, Burk O, et al. The genetic determinants of the CYP3A5 polymorphism. Pharmacogenetics 2001; 11(9): 773–9

    Article  PubMed  CAS  Google Scholar 

  192. Lamba JK, Lin YS, Schuetz EG, et al. Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev 2002; 54(10): 1271–94

    Article  PubMed  CAS  Google Scholar 

  193. Amirimani B, Walker AH, Weber BL, et al. Response: modification of clinical presentation of prostrate tumors by a novel genetic variant in CYP3A4. J Natl Cancer Inst 1999; 91: 1588–90

    Article  PubMed  Google Scholar 

  194. Kurata Y, Ieiri I, Kimura M, et al. Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P-glycoprotein. Clin Pharmacol Ther 2002; 72(2): 209–19

    Article  PubMed  CAS  Google Scholar 

  195. Chowbay B, Cumaraswamy S, Cheung YB, et al. Genetic polymorphisms in MDR1 and CYP3A4 genes in Asians and the influence of MDR1 haplotypes on cyclosporin disposition in heart transplant recipients. Pharmacogenetics 2003; 13(2): 89–95

    Article  PubMed  CAS  Google Scholar 

  196. Hoffmeyer S, Burk O, von Richter O, et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 2000; 97(7): 3473–8

    Article  PubMed  CAS  Google Scholar 

  197. Lin JH, Yamazaki M. Role of p-glycoprotein in pharmacokinetics: clinical implications. Clin Pharmacokinet 2003; 42(1): 59–98

    Article  PubMed  CAS  Google Scholar 

  198. Fredericks S, Holt DW, MacPhee IAM. The pharmacogenetics of immunosuppression for organ transplantation. Am J Pharmacogenomics 2003; 3(5): 291–301

    Article  PubMed  CAS  Google Scholar 

  199. Kaplan B, Lown K, Craig R, et al. Low bioavailability of cyclosporine microemulsion and tacrolimus in a small bowel transplant recipient: possible relationship to intestinal P-glycoprotein activity. Transplantation 1999; 67(2): 333–5

    Article  PubMed  CAS  Google Scholar 

  200. Hashida T, Masuda S, Uemoto S, et al. Pharmacokinetic and prognostic significance of intestinal MDR1 expression in recipients of living-donor liver transplantation. Clin Pharmacol Ther 2001; 69(5): 308–16

    Article  PubMed  CAS  Google Scholar 

  201. Masuda S, Uemoto S, Hashida T, et al. Effect of intestinal P-glycoprotein on daily tacrolimus trough level in a living-donor small bowel recipient. Clin Pharmacol Ther 2000; 68(1): 98–103

    Article  PubMed  CAS  Google Scholar 

  202. Hebert MF. Contributions of hepatic and intestinal metabolism and P-glycoprotein to cyclosporine and tacrolimus oral drug delivery. Adv Drug Deliv Rev 1997; 27(2–3): 201–14

    Article  PubMed  CAS  Google Scholar 

  203. Tett SE, Holford NHG, McLachlan AJ. Population pharmacokinetics and pharmacodynamics: an underutilized resource. Drug Inf J 1998; 32: 693–710

    Article  Google Scholar 

  204. Minto C, Schnider T. Expanding clinical applications of population pharmacodynamic modelling. Br J Clin Pharmacol 1998; 46(4): 321–33

    Article  PubMed  CAS  Google Scholar 

  205. Williams PJ, Ette EI. The role of population pharmacokinetics in drug development in light of the Food and Drug Administration’s ‘Guidance for Industry: population pharmacokinetic’. Clin Pharmacokinet 2000; 39(6): 385–95

    Article  PubMed  CAS  Google Scholar 

  206. Sheiner LB, Rosenberg B, Marathe VV. Estimation of population characteristics of pharmacokinetic parameters from routine clinical data. J Pharmacokinet Biopharm 1977; 5(5): 445–79

    PubMed  CAS  Google Scholar 

  207. Thomson AH, Whiting B. Bayesian parameter estimation and population pharmacokinetics. Clin Pharmacokinet 1992; 22(6): 447–67

    Article  PubMed  CAS  Google Scholar 

  208. Sam WJ, Aw M, Quak SH, et al. Population pharmacokinetics of tacrolimus in Asian paediatric liver transplant patients. Br J Clin Pharmacol 2000; 50(6): 531–41

    Article  PubMed  CAS  Google Scholar 

  209. Garcia Sanchez MJ, Manzanares C, Santos-Buelga D, et al. Covariate effects on the apparent clearance of tacrolimus in paediatric liver transplant patients undergoing conversion therapy. Clin Pharmacokinet 2001; 40(1): 63–71

    Article  PubMed  CAS  Google Scholar 

  210. Staatz CE, Taylor PJ, Lynch SV, et al. Population pharmacokinetics of tacrolimus in children who receive cut- down or full liver transplants. Transplantation 2001; 72(6): 1056–61

    Article  PubMed  CAS  Google Scholar 

  211. Mekki QA, Lee CC. Population pharmacokinetics of tacrolimus (FK506) in liver transplant patients [abstract]. Clin Pharmacol Ther 1994; 55(2): 162

    Google Scholar 

  212. Bruce NJ, Thomson AH, Elliott HL. Population pharmacokinetics of tacrolimus in liver transplant patients [online]. Available from URL: http://www.page-meeting.org/page/page95/abstract/abstract.html [Accessed 2004 Jun 24]

  213. Macchi-Andanson M, Charpiat B, Jelliffe RW, et al. Failure of traditional trough levels to predict tacrolimus concentrations. Ther Drug Monit 2001; 23(2): 129–33

    Article  PubMed  CAS  Google Scholar 

  214. Staatz CE, Willis C, Taylor PJ, et al. Towards better outcomes with tacrolimus therapy: population pharmacokinetics and individualised dosage prediction in adult liver transplantation. Liver Transpl 2003; 9: 130–7

    Article  PubMed  Google Scholar 

  215. Fukatsu S, Yano I, Igarashi T, et al. Population pharmacokinetics of tacrolimus in adult recipients receiving living-donor liver transplantation. Eur J Clin Pharmacol 2001; 57(6–7): 479–84

    PubMed  CAS  Google Scholar 

  216. Staatz CE, Willis C, Taylor PJ, et al. Population pharmacokinetics of tacrolimus in adult kidney transplant recipients. Clin Pharmacol Ther 2002; 72(6): 660–9

    Article  PubMed  CAS  Google Scholar 

  217. Willis C, Staatz CE, Tett SE. Bayesian forecasting and prediction of tacrolimus concentrations in pediatric liver and adult renal transplant recipients. Ther Drug Monit 2003; 25: 158–66

    Article  PubMed  CAS  Google Scholar 

  218. Prasad TN, Stiff DD, Subbotina N, et al. FK 506 (tacrolimus) metabolism by rat liver microsomes and its inhibition by other drugs. Res Commun Chem Pathol Pharmacol 1994; 84(1): 35–46

    PubMed  CAS  Google Scholar 

  219. Christians U, Schmidt G, Bader A, et al. Identification of drugs inhibiting the in vitro metabolism of tacrolimus by human liver microsomes. Br J Clin Pharmacol 1996; 41(3): 187–90

    Article  PubMed  CAS  Google Scholar 

  220. Iwasaki K, Matsuda H, Nagase K, et al. Effects of twenty-three drugs on the metabolism of FK506 by human liver microsomes. Res Commun Chem Pathol Pharmacol 1993; 82(2): 209–16

    PubMed  CAS  Google Scholar 

  221. Matsuda H, Iwasaki K, Shiraga T, et al. Interactions of FK506 (tacrolimus) with clinically important drugs. Res Commun Mol Pathol Pharmacol 1996; 91(1): 57–64

    PubMed  CAS  Google Scholar 

  222. Mignat C. Clinically significant drug interactions with new immunosuppressive agents. Drug Saf 1997; 16(4): 267–78

    Article  PubMed  CAS  Google Scholar 

  223. Rui X, Flowers J, Warty V, et al. Drug interactions with FK506 [abstract]. Pharm Res 1992; 9(10): S314

    Google Scholar 

  224. Spencer CM, Goa KL, Gillis JC. Tacrolimus: an update of its pharmacology and clinical efficacy in the management of organ transplantation. Drugs 1997; 54(6): 925–75

    Article  PubMed  CAS  Google Scholar 

  225. Van Gelder T. Drug interactions with tacrolimus. Drug Saf 2002; 25(10): 707–12

    Article  PubMed  Google Scholar 

  226. European FK506 Multicentre Liver Study Group. Randomised trial comparing tacrolimus (FK506) and cyclosporin in prevention of liver allograft rejection. Lancet 1994; 344: 423–8

    Article  Google Scholar 

  227. The US Multicenter FK506 Liver Study Group. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression in liver transplantation. N Engl J Med 1994; 331: 1110–5

    Article  Google Scholar 

  228. Mayer AD, Dmitrewski J, Squifflet JP, et al. Multicenter randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of renal allograft rejection: a report of the European Tacrolimus Multicenter Renal Study Group. Transplantation 1997; 64(3): 436–43

    Article  PubMed  CAS  Google Scholar 

  229. Pirsch JD, Miller J, Deierhoi MH, et al. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group. Transplantation 1997; 63(7): 977–83

    Article  PubMed  CAS  Google Scholar 

  230. Williams R, Neuhaus P, Bismuth H, et al. Two-year data from the European multicentre tacrolimus (FK506) liver study. Transpl Int 1996; 9 Suppl. 1: S144–50

    Article  PubMed  CAS  Google Scholar 

  231. Mor E, Yussim A, Chodoff L, et al. New immunosuppressive agents for maintenance therapy in organ transplantation: focus on adverse effects. BioDrugs 1997; 16(4): 242–57

    Google Scholar 

  232. Henry ML. Cyclosporine and tacrolimus (FK506): a comparison of efficacy and safety profiles. Clin Transplant 1999; 13(3): 209–20

    Article  PubMed  CAS  Google Scholar 

  233. Fung JJ, Todo S, Tzakis A, et al. Conversion of liver allograft recipients from cyclosporine to FK 506- based immunosuppression: benefits and pitfalls. Transplant Proc 1991; 23(1 Pt 1): 14–21

    PubMed  CAS  Google Scholar 

  234. Jain A, McCauley J, Kashyap R. Incidence of end-stage renal failure amongst long-term survival of primary liver transplant recipients under tacrolimus: adults and children [abstract]. Transplantation 1998; 65: S24

    Article  Google Scholar 

  235. Kelly PA, Burckart GJ, Venkataramanan R. Tacrolimus: a new immuosuppressive agent. Am J Health Syst Pharm 1995; 52(14): 1521–35

    PubMed  CAS  Google Scholar 

  236. Eidelman BH, Abu-Elmagd K, Wilson J, et al. Neurologic complications of FK 506. Transplant Proc 1991; 23(6): 3175–8

    PubMed  CAS  Google Scholar 

  237. Chang CWJ. Neurological complications of critical illness and transplantation. Curr Opin Crit Care 1999; 5(2): 112–8

    Article  Google Scholar 

  238. Mueller AR, Platz KP, Christe W, et al. Severe neurotoxicity after liver transplantation: association between FK 506 therapy and hepatitis C virus disease. Transplant Proc 1994; 26(6): 3131–2

    PubMed  CAS  Google Scholar 

  239. Jindal RM, Sidner RA, Milgrom ML. Post-transplant diabetes mellitus: the role of immunosuppression. Drug Saf 1997; 16(4): 242–57

    Article  PubMed  CAS  Google Scholar 

  240. Bonomini V, For the Italian-Spanish Tacrolimus Study Group. Low rejection rates with tacrolimus-based dual and triple regimens following renal transplantation [abstract]. J Am Soc Nephrol 1999; 10: 720A

    Google Scholar 

  241. Peters DH, Fitton A, Plosker GL, et al. Tacrolimus: a review of its pharmacology, and therapeutic potential in hepatic and renal transplantation. Drugs 1993; 46(4): 746–94

    Article  PubMed  CAS  Google Scholar 

  242. Abouljoud MS, Levy MF, Klintmalm GB. Hyperlipidemia after liver transplantation: long-term results of the FK506/cyclosporine A US Multicenter trial. US Multicenter Study Group. Transplant Proc 1995; 27(1): 1121–3

    PubMed  CAS  Google Scholar 

  243. Burke GW, Ciancio G, Alejandro R, et al. Cholesterol control: long-term benefit of pancreas-kidney transplantation with FK 506 immunosuppression. Transplant Proc 1998; 30(2): 513–4

    Article  PubMed  CAS  Google Scholar 

  244. Canzanello VJ, Schwartz L, Taler SJ, et al. Evolution of cardiovascular risk after liver transplantation: a comparison of cyclosporine A and tacrolimus (FK506). Liver Transpl Surg 1997; 3(1): 1–9

    Article  PubMed  CAS  Google Scholar 

  245. Claesson K, Mayer AD, Squifflet JP, et al. Lipoprotein patterns in renal transplant patients: a comparison between FK 506 and cyclosporine A patients. Transplant Proc 1998; 30(4): 1292–4

    Article  PubMed  CAS  Google Scholar 

  246. Friemann S, Feuring E, Padberg W, et al. Improvement of nephrotoxicity, hypertension, and lipid metabolism after conversion of kidney transplant recipients from cyclosporine to tacrolimus. Transplant Proc 1998; 30(4): 1240–2

    Article  PubMed  CAS  Google Scholar 

  247. Guckelberger O, Bechstein WO, Neuhaus R, et al. Cardiovascular risk factors in long-term follow-up after orthotopic liver transplantation. Clin Transplant 1997; 11(1): 60–5

    PubMed  CAS  Google Scholar 

  248. McCune TR, Thacker LR, Peters TG, et al. Effects of tacrolimus on hyperlipidemia after successful renal transplantation: a Southeastern Organ Procurement Foundation multicenter clinical study. Transplantation 1998; 65(1): 87–92

    Article  PubMed  CAS  Google Scholar 

  249. Penson MG, Winter WE, Fricker FJ, et al. Tacrolimus-based triple-drug immunosuppression minimizes serum lipid elevations in pediatric cardiac transplant recipients. J Heart Lung Transplant 1999; 18(7): 707–13

    Article  PubMed  CAS  Google Scholar 

  250. Taylor DO, Barr ML, Radovancevic B, et al. A randomized, multicenter comparison of tacrolimus and cyclosporine immunosuppressive regimens in cardiac transplantation: decreased hyperlipidemia and hypertension with tacrolimus. J Heart Lung Transplant 1999; 18(4): 336–45

    Article  PubMed  CAS  Google Scholar 

  251. Varghese Z, Fernando RL, Turakhia G, et al. Oxidizability of low-density lipoproteins from Neoral and tacrolimus- treated renal transplant patients. Transplant Proc 1998; 30(5): 2043–6

    Article  PubMed  CAS  Google Scholar 

  252. Fagiuoli S, Gasbarrini A, Azzarone A, et al. FK 506: a new immunosuppressive agent for organ transplantation: pharmacology, mechanism of action and clinical applications. Ital J Gastroenterol 1992; 24(6): 355–60

    PubMed  CAS  Google Scholar 

  253. Li PKT, Nicholls MG, Lai KN. The complications of newer transplant antirejection drugs: treatment with cyclosporin-A, OKT-3 and FK506. Adverse Drug React Acute Poisoning Rev 1990; 9: 123–55

    PubMed  CAS  Google Scholar 

  254. McCauley J, Fung J, Jain A, et al. The effects of FK 506 on renal function after liver transplantation. Transplant Proc 1990; 22(1): 17–20

    PubMed  CAS  Google Scholar 

  255. Niederstadt C, Steinhoff J, Erbsloh-Moller B, et al. Effect of FK506 on magnesium homeostasis after renal transplantation. Transplant Proc 1997; 29(7): 3161–2

    Article  PubMed  CAS  Google Scholar 

  256. Mayer AD. Four-year follow-up of the European Tacrolimus Multicenter Renal Study. Transplant Proc 1999; 31(7A): 27–8S

    Article  Google Scholar 

  257. Tzakis AG, Fung JJ, Todo S, et al. Use of FK 506 in pediatric patients. Transplant Proc 1991; 23(1 Pt 2): 924–7

    PubMed  CAS  Google Scholar 

  258. Tzakis AG, Reyes J, Todo S, et al. Two-year experience with FK 506 in pediatric patients. Transplant Proc 1993; 25(1 Pt 1): 619–21

    PubMed  CAS  Google Scholar 

  259. Sokal EM, Antunes H, Beguin C, et al. Early signs and risk factors for the increased incidence of Epstein-Barr virus-related posttransplant lymphoproliferative diseases in pediatric liver transplant recipients treated with tacrolimus. Transplantation 1997; 64(10): 1438–42

    Article  PubMed  CAS  Google Scholar 

  260. Shapiro R, Scantlebury VP, Jordan ML, et al. Pediatric renal transplantation under tacrolimus-based immunosuppression. Transplantation 1999; 67(2): 299–303

    Article  PubMed  CAS  Google Scholar 

  261. Jain A, Reyes J, Kashyap R, et al. Liver transplantation under tacrolimus in infants, children, adults, and seniors: long-term results, survival, and adverse events in 1000 consecutive patients. Transplant Proc 1998; 30(4): 1403–4

    Article  PubMed  CAS  Google Scholar 

  262. Inomata Y, Tanaka K, Egawa H, et al. The evolution of immunosuppression with FK506 in pediatric living-related liver transplantation. Transplantation 1996; 61(2): 247–52

    Article  PubMed  CAS  Google Scholar 

  263. So S, The US Multicentre FK506 Liver Study Group. Post-transplant lymphoproliferative disease (PTLD) in tacrolimus-treated liver transplant patients [abstract 207]. Proceedings of the 15th Annual Meeting of the American Society of Transplant Physicians; 1996 May 26–30; Dallas: 136

  264. Newell KA, Alonso EM, Whitington PF, et al. Posttransplant lymphoproliferative disease in pediatric liver transplantation: interplay between primary Epstein-Barr virus infection and immunosuppression. Transplantation 1996; 62(3): 370–5

    Article  PubMed  CAS  Google Scholar 

  265. Paolillo JA, Wagner K, Boyle GE, et al. Post-transplant diabetes mellitus in paediatric thoracic organ recipients receiving tacrolimus-based immunosuppression [abstract]. Transplantation 1999; 67(7): S230

    Article  Google Scholar 

  266. Moxey-Mims MM, Kay C, Light JA, et al. Increased incidence of insulin-dependent diabetes mellitus in pediatric renal transplant patients receiving tacrolimus (FK506). Transplantation 1998; 65(5): 617–9

    Article  PubMed  CAS  Google Scholar 

  267. Backman L, Levy MF, Klintmalm G. Whole-blood and plasma levels of FK 506 after liver transplantation: results from the US Multicenter Trial. FK506 Multicenter Study Group. Transplant Proc 1995; 27(1): 1124

    CAS  Google Scholar 

  268. Backman L, Nicar M, Levy M, et al. FK506 trough levels in whole blood and plasma in liver transplant recipients: correlation with clinical events and side effects. Transplantation 1994; 57(4): 519–25

    PubMed  CAS  Google Scholar 

  269. Bottiger Y, Brattstrom C, Tyden G, et al. Tacrolimus whole blood concentrations correlate closely to side-effects in renal transplant recipients. Br J Clin Pharmacol 1999; 48(3): 445–8

    Article  PubMed  CAS  Google Scholar 

  270. Jain AB, Todo S, Fung JJ, et al. Correlation of rejection episodes with FK 506 dosage, FK 506 level, and steroids following primary orthotopic liver transplant. Transplant Proc 1991; 23(6): 3023–5

    PubMed  CAS  Google Scholar 

  271. Japanese study of FK 506 on kidney transplantation: the benefit of monitoring the whole blood FK 506 concentration. Japanese FK 506 Study Group. Transplant Proc 1991; 23(6): 3085–8

    Google Scholar 

  272. Kershner RP, Fitzsimmons WE. Relationship of FK506 whole blood concentrations and efficacy and toxicity after liver and kidney transplantation. Transplantation 1996; 62(7): 920–6

    Article  PubMed  CAS  Google Scholar 

  273. Laskow DA, Vincenti F, Neylan JF, et al. An open-label, concentration-ranging trial of FK506 in primary kidney transplantation: a report of the United States Multicenter FK506 Kidney Transplant Group. Transplantation 1996; 62(7): 900–5

    Article  PubMed  CAS  Google Scholar 

  274. Przepiorka D, Nash RA, Wingard JR, et al. Relationship of tacrolimus whole blood levels to efficacy and safety outcomes after unrelated donor marrow transplantation. Biol Blood Marrow Transplant 1999; 5(2): 94–7

    Article  PubMed  CAS  Google Scholar 

  275. Sandborn WJ, Lawson GM, Cody TJ, et al. Early cellular rejection after orthotopic liver transplantation correlates with low concentrations of FK506 in hepatic tissue. Hepatology 1995; 21(1): 70–6

    PubMed  CAS  Google Scholar 

  276. Schwartz M, Holst B, Facklam D, et al. FK 506 in liver transplantation: correlation of whole blood levels with efficacy and toxicity. The US Multicenter FK 506 Dose Optimization. Transplant Proc 1995; 27(1): 1107

    CAS  Google Scholar 

  277. Takahara S, Kokado Y, Kameoka H, et al. Monitoring of FK 506 blood levels in kidney transplant recipients. Transplant Proc 1994; 26(4): 2106–8

    PubMed  CAS  Google Scholar 

  278. Undre NA, van Hooff J, Christiaans M, et al. Low systemic exposure to tacrolimus correlates with acute rejection. Transplant Proc 1999; 31(1–2): 296–8

    Article  PubMed  CAS  Google Scholar 

  279. Winkler M, Pichlmayr R, Neuhaus P, et al. Optimal FK 506 dosage in patients under primary immunosuppression following liver transplantation. Transpl Int 1994; 7 Suppl. 1: S58–63

    Article  PubMed  Google Scholar 

  280. Winkler M, Christians U. A risk-benefit assessment of tacrolimus in transplantation. Drug Saf 1995; 12(5): 348–57

    Article  PubMed  CAS  Google Scholar 

  281. Venkataramanan R, Shaw LM, Sarkozi L, et al. Clinical utility of monitoring tacrolimus blood concentrations in liver transplant patients. J Clin Pharmacol 2001; 41(5): 542–51

    Article  PubMed  CAS  Google Scholar 

  282. Staatz C, Taylor P, Tett S. Low tacrolimus concentrations and increased risk of early acute rejection in adult renal transplantation. Nephrol Dial Transplant 2001; 16(9): 1905–9

    Article  PubMed  CAS  Google Scholar 

  283. Winkler M, Wonigeit K, Undre N, et al. Comparison of plasma vs whole blood as matrix for FK 506 drug level monitoring. Transplant Proc 1995; 27(1): 822–5

    PubMed  CAS  Google Scholar 

  284. Ringe B, Braun F, Lorf T, et al. Tacrolimus and mycophenolate mofetil in clinical liver transplantation: experience with a steroid-sparing concept. Transplant Proc 1998; 30(4): 1415–6

    Article  PubMed  CAS  Google Scholar 

  285. Tsunoda SM, Aweeka FT. The use of therapeutic drug monitoring to optimise immunosuppressive therapy. Clin Pharmacokinet 1996; 30(2): 107–40

    Article  PubMed  CAS  Google Scholar 

  286. Armstrong VW, Oellerich M. New developments in the immunosuppressive drug monitoring of cyclosporine, tacrolimus, and azathioprine. Clin Biochem 2001; 34(1): 9–16

    Article  PubMed  CAS  Google Scholar 

  287. Shaw LM, Holt DW, Keown P, et al. Current opinions on therapeutic drug monitoring of immunosuppressive drugs. Clin Ther 1999; 21(10): 1632–52

    Article  PubMed  CAS  Google Scholar 

  288. Kahan BD, Keown P, Levy GA, et al. Therapeutic drug monitoring of immunosuppressant drugs in clinical practice. Clin Ther 2002; 24(3): 330–50

    Article  PubMed  CAS  Google Scholar 

  289. Oellerich M, Armstrong VW, Schutz E, et al. Therapeutic drug monitoring of cyclosporine and tacrolimus: update on Lake Louise Consensus Conference on cyclosporin and tacrolimus. Clin Biochem 1998; 31(5): 309–16

    Article  PubMed  CAS  Google Scholar 

  290. Alak AM, Moy S, Cook M, et al. An HPLC/MS/MS assay for tacrolimus in patient blood samples: correlation with results of an ELISA assay. J Pharm Biomed Anal 1997; 16(1): 7–13

    Article  PubMed  CAS  Google Scholar 

  291. Christians U, Jacobsen W, Serkova N, et al. Automated, fast and sensitive quantification of drugs in blood by liquid chromatography-mass spectrometry with on-line extraction: immunosuppressants. J Chromatogr B Biomed Sci Appl 2000; 748(1): 41–53

    Article  PubMed  CAS  Google Scholar 

  292. Deters M, Kirchner G, Resch K, et al. Simultaneous quantification of sirolimus, everolimus, tacrolimus and cyclosporine by liquid chromatography-mass spectrometry (LC-MS). Clin Chem Lab Med 2002; 40(3): 285–92

    Article  PubMed  CAS  Google Scholar 

  293. Keevil BG, McCann SJ, Cooper DP, et al. Evaluation of a rapid micro-scale assay for tacrolimus by liquid chromatographytandem mass spectrometry. Ann Clin Biochem 2002; 39 (Pt 5): 487–92

    Article  PubMed  CAS  Google Scholar 

  294. Lensmeyer GL, Poquette MA. Therapeutic monitoring of tacrolimus concentrations in blood: semi-automated extraction and liquid chromatography-electrospray ionization mass spectrometry. Ther Drug Monit 2001; 23(3): 239–49

    Article  PubMed  CAS  Google Scholar 

  295. Salm P, Taylor PJ, Clark A, et al. High-performance liquid chromatography-tandem mass spectrometry as a reference for analysis of tacrolimus to assess two immunoassays in patients with liver and renal transplants. Ther Drug Monit 1997; 19(6): 694–700

    Article  PubMed  CAS  Google Scholar 

  296. Streit F, Armstrong VW, Oellerich M. Rapid liquid chromatography-tandem mass spectrometry routine method for simultaneous determination of sirolimus, everolimus, tacrolimus, and cyclosporin A in whole blood. Clin Chem 2002; 48(6 Pt 1): 955–8

    PubMed  CAS  Google Scholar 

  297. Taylor PJ, Salm P, Lynch SV, et al. Simultaneous quantification of tacrolimus and sirolimus, in human blood, by highperformance liquid chromatography-tandem mass spectrometry. Ther Drug Monit 2000; 22(5): 608–12

    Article  PubMed  CAS  Google Scholar 

  298. Volosov A, Napoli KL, Soldin SJ. Simultaneous simple and fast quantification of three major immunosuppressants by liquid chromatography: tandem mass-spectrometry. Clin Biochem 2001; 34(4): 285–90

    Article  PubMed  CAS  Google Scholar 

  299. Zhang Q, Simpson J, Aboleneen HI. A specific method for the measurement of tacrolimus in human whole blood by liquid chromatography/tandem mass spectrometry. Ther Drug Monit 1997; 19(4): 470–6

    Article  PubMed  CAS  Google Scholar 

  300. Braun F, Peters B, Schutz E, et al. Therapeutic drug monitoring of tacrolimus early after liver transplantation. Transplant Proc 2002; 34(5): 1538–9

    Article  PubMed  CAS  Google Scholar 

  301. Jorgensen K, Povlsen J, Maden S, et al. C2 (2-h) levels are not superior to trough levels as estimates of the area under the curve in tacrolimus-treated renal-transplant patients. Nephrol Dial Transplant 2002; 17: 1487–90

    Article  PubMed  CAS  Google Scholar 

  302. Cantarovich M, Fridell J, Barkun J, et al. Optimal time points for the prediction of the area-under-the-curve in liver transplant patients receiving tacrolimus. Transplant Proc 1998; 30(4): 1460–1

    Article  PubMed  CAS  Google Scholar 

  303. Wong KM, Shek CC, Chau KF, et al. Abbreviated tacrolimus area-under-the-curve monitoring for renal transplant recipients. Am J Kidney Dis 2000; 35: 660–6

    Article  PubMed  CAS  Google Scholar 

  304. Pisitkun T, Eiam-Ong S, Chusil S, et al. The roles of C4 and AUC0–4 in monitoring of tacrolimus in stable kidney transplant patients. Transplant Proc 2002; 34: 3173–5

    Article  PubMed  CAS  Google Scholar 

  305. Ku YM, Min DI. An abbreviated area-under-the-curve monitoring for tacrolimus in patients with liver transplants. Ther Drug Monit 1998; 20(2): 219–23

    Article  PubMed  CAS  Google Scholar 

  306. Stolk LM, Van Duijnhoven EM, Christiaans MH, et al. Evaluation of prediction of tacrolimus area under the curve by trough concentrations [abstract]. Br J Clin Pharmacol 2002; 53(5): 554

    Article  Google Scholar 

  307. Jorgensen KA, Povlsen JV, Poulsen JH. Optimal time for determination of blood tacrolimus level. Transplant Proc 2001; 33(7–8): 3164–5

    Article  PubMed  CAS  Google Scholar 

  308. Uchida K, Tominaga Y, Haba T, et al. Usefulness of monitoring of AUC(0–4h) during the induction period of immunosuppressive therapy with tacrolimus after renal transplantation. Transplant Proc 2002; 34(5): 1736–7

    Article  PubMed  CAS  Google Scholar 

  309. Dambrin C, Klupp J, Morris RE. Pharmacodynamics of immunosuppressive drugs. Curr Opin Immunol 2000; 12(5): 557–62

    Article  PubMed  CAS  Google Scholar 

  310. Thomson AW, Bonham CA, Zeevi A. Mode of action of tacrolimus (FK506): molecular and cellular mechanisms. Ther Drug Monit 1995; 17(6): 584–91

    Article  PubMed  CAS  Google Scholar 

  311. Halloran PF. Molecular mechanisms of new immunosuppressants. Clin Transplant 1996; 10(1 Pt 2): 118–23

    PubMed  CAS  Google Scholar 

  312. Halloran PF, Kung L, Noujaim J. Calcineurin and the biological effect of cyclosporine and tacrolimus. Transplant Proc 1998; 30(5): 2167–70

    Article  PubMed  CAS  Google Scholar 

  313. Yatscoff RW, Aspeslet LJ. The monitoring of immunosuppressive drugs: a pharmacodynamic approach. Ther Drug Monit 1998; 20(5): 459–63

    Article  PubMed  CAS  Google Scholar 

  314. Koefoed-Nielsen P, Jorgensen K. Alterations in calcineurin phosphatase activity in tacrolimus-treated renal transplant patients. Transplant Proc 2002; 34(5): 1743–4

    Article  PubMed  CAS  Google Scholar 

  315. Koefoed-Nielsen PB, Gesualdo MB, Poulsen JH, et al. Blood tacrolimus levels and calcineurin phosphatase activity early after renal transplantation. Am J Transplant 2002; 2(2): 173–8

    Article  PubMed  CAS  Google Scholar 

  316. Kung L, Halloran PF. Immunophilins may limit calcineurin inhibition by cyclosporine and tacrolimus at high drug concentrations. Transplantation 2000; 70(2): 327–35

    Article  PubMed  CAS  Google Scholar 

  317. Dumont RJ, Ensom MH. Methods for clinical monitoring of cyclosporin in transplant patients. Clin Pharmacokinet 2000; 38(5): 427–47

    Article  PubMed  CAS  Google Scholar 

  318. Andersson U, Hallden G, Persson U, et al. Enumeration of IFN-gamma-producing cells by flow cytometry: comparison with fluorescence microscopy. J Immunol Methods 1988; 112(1): 139–42

    Article  PubMed  CAS  Google Scholar 

  319. Jung T, Schauer U, Heusser C, et al. Detection of intracellular cytokines by flow cytometry. J Immunol Methods 1993; 159(1-2): 197–207

    Article  PubMed  CAS  Google Scholar 

  320. Assenmacher M, Schmitz J, Radbruch A. Flow cytometric determination of cytokines in activated murine T helper lymphocytes: expression of interleukin-10 in interferon-gamma and in interleukin-4-expressing cells. Eur J Immunol 1994; 24(5): 1097–101

    Article  PubMed  CAS  Google Scholar 

  321. Picker LJ, Singh MK, Zdraveski Z, et al. Direct demonstration of cytokine synthesis heterogeneity among human memory/effector T cells by flow cytometry. Blood 1995; 86(4): 1408–19

    PubMed  CAS  Google Scholar 

  322. Prussin C, Metcalfe DD. Detection of intracytoplasmic cytokine using flow cytometry and directly conjugated anti-cytokine antibodies. J Immunol Methods 1995; 188(1): 117–28

    Article  PubMed  CAS  Google Scholar 

  323. Rostaing L, Puyoo O, Tkaczuk J, et al. Differences in Type 1 and Type 2 intracytoplasmic cytokines, detected by flow cytometry, according to immunosuppression (cyclosporine A vs tacrolimus) in stable renal allograft recipients. Clin Transplant 1999; 13(5): 400–9

    Article  PubMed  CAS  Google Scholar 

  324. Sewell WA, North ME, Webster AD, et al. Determination of intracellular cytokines by flow-cytometry following whole-blood culture. J Immunol Methods 1997; 209(1): 67–74

    Article  PubMed  CAS  Google Scholar 

  325. van den Berg AP, Twilhaar WN, van Son WJ, et al. Quantification of immunosuppression by flow cytometric measurement of intracellular cytokine synthesis. Transpl Int 1998; 11 Suppl. 1: S318–21

    PubMed  Google Scholar 

  326. Ahmed M, Venkataraman R, Logar AJ, et al. Quantitation of immunosuppression by tacrolimus using flow cytometric analysis of interleukin-2 and interferon-gamma inhibition in CD8(−) and CD8(+) peripheral blood T cells. Ther Drug Monit 2001; 23(4): 354–62

    Article  PubMed  CAS  Google Scholar 

  327. van den Berg AP, van Son WJ, Haagsma EB, et al. Prediction of the inhibition of IL-2 production by calcineurin inhibitors. Transplant Proc 2001; 33(1–2): 1076–7

    Article  PubMed  Google Scholar 

  328. Ahmed M, Venkataramanan R, Logar AJ, et al. Quantitation of immunosuppression by FK506 using flow cytometric analysis of IL-2 and INF-gamma inhibition in peripheral blood cells [abstract]. Transplantation 2000; 69: S393

    Article  Google Scholar 

  329. Klupp J, Dambrin C, Regieli J, et al. New approach in drug development: whole blood pharmacodynamic assays reflect biological activities of tacrolimus. Transplant Proc 2001; 33(3): 2172

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

Christine Staatz and Susan Tett do not have any pharmaceutical industry affiliation and have no pecuniary interests (personal or professional), grants or other potential conflicts of interest with any pharmaceutical company.

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Staatz, C.E., Tett, S.E. Clinical Pharmacokinetics and Pharmacodynamics of Tacrolimus in Solid Organ Transplantation. Clin Pharmacokinet 43, 623–653 (2004). https://doi.org/10.2165/00003088-200443100-00001

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