Continuing Medical Education: Cutaneous BiologyDrug interactions: Proteins, pumps, and P-450s☆,☆☆,★
Section snippets
The assessment of risk in the clinical outcome of drug interactions
The clinical importance of specific drug interactions is often either overestimated or underestimated because these assessments are largely based on clinical experience in using the particular drug combination.7 The clinical outcome of most drug interactions is highly situational. Most patients who receive drugs with the potential for interactions do not experience adverse effects. Emphasis should be placed on those factors that increase or decrease the risk to a given patient.
Physicians need
Levels of evidence
Drug interaction literature is often confusing because of poorly substantiated claims.9 Confusion occurs as a result of inaccurate or cursory evaluation of published cases or inappropriate extrapolations from the literature. Metabolic drug interactions are a major source of clinical problems, but their investigation during drug development is often incomplete. In vitro studies provide very accurate data on the interactions of drugs with selective cytochrome P-450 (CYP) isozymes, but their
Absorption
The mechanisms of most drug interactions that alter absorption involve the formation of drug complexes that reduce absorption or cause alterations in the gastric pH and/or changes in gastrointestinal motility that alter transit time.12
Common drugs that form complexes with other drugs include antacids, sucralfate, and cholesterol-binding resins. When mycophenolate mofetil and iron ion preparations were administered concomitantly, a remarkable decrease of mycophenolate mofetil absorption was
P-glycoprotein
Membrane-bound transport systems may also determine drug disposition.16 P-glycoprotein (PGP) is an adenosine triphosphate (ATP)-dependent plasma membrane glycoprotein belonging to the superfamily of ATP-binding cassette transporters.17 The MDR1 gene in humans encodes membrane glycoproteins that function as drug transporters and therefore affect both drug absorption and elimination. High levels of PGP are found in superficial columnar epithelial cells of the small intestine, apical surface
Distribution
Drugs that are highly protein bound (>90%) may cause drug interactions based on alterations in drug distribution. When one drug displaces another from plasma protein-binding sites, the free serum concentration of the displaced drug is increased and its pharmacologic effect increases. However, the unbound fraction of the drug is not only more available to sites of action but is also more readily eliminated. Any enhanced pharmacologic effect occurs only transiently because of a compensatory
Cytochrome P-450 enzymes
Most relevant drug interactions in dermatology have a pharmacokinetic mechanism, and recent studies suggest that the most clinically important drug interactions involve hepatic drug biotransformation pathways catabolized by the cytochrome P-450 family of enzymes. When drugs are administered, they are metabolized through a series of reactions to enhance drug hydrophilicity and facilitate drug excretion. These drug biotransformation reactions are grouped into two phases, phase I and phase II.
Metabolism
The most clinically relevant drug interactions are caused by alterations in drug metabolism (Tables IV-XII).
Substrates of CYP2D6 Empty Cell Inhibitors of CYP2D6 Analgesics SSRI antidepressants Allylamine antifungal Codeine Fluoxetine Terbinafine Dextromethorphan Maprotiline Ethylmorphine Mianserin Antiarrythmics Oxycodone Norfluoxetine Amiodarone Nortriptyline Propafenone Antiarrythmics Paroxetine Quinidine Amiodarone Trazodone* Encainide Trimipramine Antipshychotic agents Flecainide
Cytochrome induction (Table VI)
Many enzymes involved in drug biotransformation are able to increase in amount and activity in response to substances known as inducers. The onset and offset of enzyme induction is gradual because the induction phase depends on the accumulation of the particular inducing agent and subsequent synthesis of new enzyme, whereas offset depends on elimination of the inducer and decay of the increased enzyme levels. This is in contrast to the effects seen with cytochrome inhibitors that have a quick
Cytochrome inhibition (Tables VII-X)
The inhibition of drug metabolism is the most important mechanism for drug interactions because it can lead to an increase in plasma drug concentration, increased drug response, and toxic effects. Inhibition of metabolism begins within the first one or two doses of the inhibitor and is maximal when a steady-state concentration of the inhibitor is achieved.
Inhibitory interactions can be either competitive or noncompetitive. An example of competitive inhibition involves the tight binding of
Genetic polymorphisms
Each of the isoenzymes of the P-450 system is under genetic control. Because of genetic polymorphism, different individuals have different levels of activity of different P-450 isoforms. Genetic polymorphism means that within a normal population, some people have a functional enzyme and others do not. People with genetically determined low levels of activity are referred to as poor metabolizers. People who have a functional enzyme are known as extensive metabolizers. There are yet others who
The assessment of risk in the clinical outcome of drug interactions
A myth that is important to dispel is that all drugs in a given class are equally susceptible to drug interactions. In fact, this is false! Understanding the differences in each drug class's potential for drug interactions is highly clinically relevant (Table XI). Drugs with little or no clinical potential for drug interactions then become safer choices. Unfortunately, standard reference textbooks often lump drug classes together as inhibitors, so the important differences of drugs within the
Pharmacogenetic variation
Pharmacogenetic variation can also occur in other drug-metabolizing enzymes. Pertinent to dermatologists, the enzyme thiopurine S-methyltransferase (TPMT) is important in the metabolism of azathioprine and 6-mercaptopurine to nontoxic metabolites. There is a 0.3% rate of homozygous deficiency of this enzyme, which puts patients receiving these drugs at great risk for toxic effects, especially myelosuppression.39 Conversely, 88% of the population is homozygous dominant for the active TPMT enzyme
Antihistamines
Terfenadine (Seldane) has been removed from the market because of its serious interactions with cardiovascular drugs. Its active acid metabolite, fexofenadine (Allegra), has taken the parent drug's place and is not associated with fatal drug interactions.40 Terfenadine was reported in 1990 to cause QT interval prolongation and torsades de pointes when given with ketoconazole.41 Serum concentrations of terfenadine were excessive, and concentrations of its main metabolite were reduced, suggesting
Conclusion
Dealing with drug interactions is a challenge in the clinic. New information appears quickly, but dermatologists must know about the drugs they use. Although no one can be expected to know all drug interactions, good resources are invaluable (eg, The Medical Letter's Handbook of Adverse Drug Interactions 2002 or a hospital drug information service). However, the Handbook is limited, as are most desk references, by class-related statements. To minimize the risk of drug-protein-drug interactions,
References (97)
- et al.
Intestinal MDR transport proteins and P-450 enzymes as barriers to oral delivery
J Controlled Release
(1999) - et al.
In vitro approaches can predict human drug metabolism
Trends Pharmacol Sci
(1993) - et al.
The role of cytochrome P450 enzymes in hepatic and extrahepatic human drug toxicity
Phamacol Ther
(1995) - et al.
Drug interactions in human neuropathic pain pharmacotherapy
Pain
(1997) - et al.
A pharmacogenetic basis for the safe and effective use of azathioprine and other thiopurine drugs in dermatologic patients
J Am Acad Dermatol
(1995) - et al.
Drug interactions with itraconazole, fluconazole, and terbinafine and their management
J Am Acad Dermatol
(1999) Harmless herbs? A review of the recent literature
Am J Med
(1998)- et al.
Acute heart transplant rejection due to Saint John's wort
Lancet
(2000) - et al.
Indinavir concentrations and St. John's wort
Lancet
(2000) - et al.
Use of alternative medicine by patients ungergoing cardiac surgery
J Thorac Cardiovasc Surg
(2000)
Herb-drug interacations: a review
Lancet
P glycoprotein system as a determinant of drug interactions: the case of digoxin-verapamil
Pharmacol Res
Drug interactions—how scared should we be?
CMAJ
Drug interactions: who warns the patients? [editorial]
CMAJ
Predictors of potential drug interactions
Hosp Pharm
Epidemiology of drug-drug interactions as a cause of hospital admissions
Drug Saf
Medication misadventures resulting in emergency department visits at an HMO medical center
Am J Health Syst Pharm
Frequency of hospitalization after exposure to known drug-drug interactions in a Medicaid population
Pharmacotherapy
Pharmacokinetic mechanisms of drug-drug and drug-food interactions in dermatology
Curr Probl Dermatol
Adverse drug interactions clinically important for the dermatologist
Arch Dermatol
Clinically significant drug interactions: recognition and understanding of common mechanisms
Curr Pract Med
Postmarketing drug surveillance: what it would take to make it work
CMAJ
Quantitative drug interactions prediction system (Q-DIPS): a dynamic computer-based method to assist in the choice of clinically relevant in vivo studies
Clin Pharmacokinet
Drug interactions: keeping it straight
Am Fam Physician
Impairment of mycophenolate mofetil absorption by iron ion
Clin Pharmacol Ther
Azole antifungal drugs
Clin Infect Dis
Drug interactions
Drug Interactions Newsletter
Drug interactions
The Medical Letter
P-glycoprotein and related transporters
Int J Clin Pharmacol Ther
Role of intestinal p-glycoprotein (mdr1) in interpatient variation in the oral bioavailabity of cyclosporine
Clin Pharmacol Ther
Ivermectin: an assessment of its pharmacology, microbiology and safety
Vet Hum Toxicol
Drug interactions
Drug Interactions Newsletter
Drug metabolism by cytochromes 450 in the liver and small bowel
Gastroenterol Clin North Am
Human cytochrome P450 enzymes
Human cytochrome P450 enzymes
Drug Metab Rev
Drug interactions
The Medical Letter
Clinically significant cytochrome P-450 drug interactions—a comment
Pharmacotherapy
Influence of gender on the pharmacokinetics and pharmacodynamics of drugs
Int J Clin Pharmacol Ther
Effects of obesity on the cytochrome P450 enzyme system
Int J Clin Pharmacol
Use of in vivo and in vitro data to estimate the likelihood of metabolic pharmacokinetic interactions
Clin Pharmacokinet
Molecular basis of polymorphic drug metabolism
J Mol Med
Genetic polymorphism of human N-acetyltransferase, cytochrome P450, glutathione-s-transferase and epoxide hydrolase enzymes: relevance to xenobiotic metabolism and toxicity
Crit Rev Toxicol
Genetic polymorphism of human n-acetyltransferase, cytochrome P450, glutathione-S-transferase, and epoxied hydrolase enzymes: relevance to xenobiotic metabolism and toxicity
Crit Rev Toxicol
Determination of CYP1A2 and NAT2 phenotypes in human populations by analysis of caffeine urinary metabolites
Pharmacogenetics
Altered patterns of drug metabolism in patients with acquired immunodeficiency syndrome
Clin Pharmacol Ther
Methotrexate in rheumatoid arthritis: indications, contraindications, efficacy and safety
Ann Intern Med
Torsades do pointes occurring in association with terfenadine use
JAMA
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Polymorphisms
2020, Comprehensive Dermatologic Drug Therapy, Fourth EditionDrug Interactions
2020, Comprehensive Dermatologic Drug Therapy, Fourth EditionThe role of genetic polymorphisms in cytochrome P450 and effects of tuberculosis co-treatment on the predictive value of CYP2B6 SNPs and on efavirenz plasma levels in adult HIV patients
2014, Antiviral ResearchCitation Excerpt :Based on this and the higher PPV observed in our analyses for CYP2B6 516T/T and 983T/T genotypes for the prediction of supra-therapeutic EFV plasma levels, we are thus suggesting the genotyping assay for CYP2B6 SNPs when deciding on EFV dosages is required. It is worth noting that observed decrease of EFV plasma levels could partly be attributed to the reported induction effect on EFV metabolizing enzymes, such as CYP2B6 and CYP3A4 by rifampicin (Burman et al., 1999; Cohen et al., 2009; Gengiah et al., 2012; Kwara et al., 2011a,b; Li and Chiang, 2006; Manzi and Shannon, 2005; Ramachandran et al., 2009; Rodríguez-Nóvoa et al., 2006; Shapiro and Shear, 2002; Szalat et al., 2007; Uttayamakul et al., 2010), which was one of the TB drugs used by the patients studied, but also to overlapping EFV auto-induction, which however, could have not contributed significantly. In fact, based on the data from his study when HIV and TB are treated concomitantly, Ngaimisi et al. (2011) demonstrated that EFV auto-induction does not exhibit significant additive or synergistic effects over and above ongoing rifampicin-based TB therapy.
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Funding sources: None.
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Disclosure: Dr Shear is a paid consultant for Roche, GlaxoSmithKline, Galderma, and Novartis.
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Reprint requests: Lori Shapiro, Division of Clinical Pharmacology, Sunnybrook and Women's College Health Science Centre, Room E-240, 2075 Bayview Ave, Toronto, Ontario, Canada M4N 3M5.