Continuing Medical Education: Cutaneous Biology
Drug interactions: Proteins, pumps, and P-450s,☆☆,

https://doi.org/10.1067/mjd.2002.126823Get rights and content

Abstract

The two major concerns in drug safety are adverse drug reactions and drug interactions. When multiple drug therapies are prescribed, drug interactions become an important consideration for patients and physicians. The life of a drug is reviewed with emphasis on absorption, distribution, metabolism, and excretion. Pharmacokinetic and pharmacodynamic mechanisms for drug interactions are reviewed. The contributions of P-glycoprotein, pharmacogenetic variation, and genetic polymorphisms to drug interactions are highlighted. Prediction of drug interactions is possible with knowledge of which agents are likely to cause alterations in drug metabolism. (J Am Acad Dermatol 2002;47:467-84.)

Learning objective: At the conclusion of this learning activity, participants should have an understanding of the life of a drug. This knowledge should help predict important potential drug interactions.

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 and inhibitors of CYP2D6

Substrates of CYP2D6Empty CellInhibitors of CYP2D6
AnalgesicsSSRI antidepressantsAllylamine antifungal
CodeineFluoxetineTerbinafine
DextromethorphanMaprotiline
EthylmorphineMianserinAntiarrythmics
OxycodoneNorfluoxetineAmiodarone
NortriptylinePropafenone
AntiarrythmicsParoxetineQuinidine
AmiodaroneTrazodone*
EncainideTrimipramineAntipshychotic 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)

  • A Fugh-Berman

    Herb-drug interacations: a review

    Lancet

    (2000)
  • M Verschraagen et al.

    P glycoprotein system as a determinant of drug interactions: the case of digoxin-verapamil

    Pharmacol Res

    (1999)
  • LE Shapiro et al.

    Drug interactions—how scared should we be?

    CMAJ

    (1999)
  • J Hoey

    Drug interactions: who warns the patients? [editorial]

    CMAJ

    (1999)
  • RA Weideman et al.

    Predictors of potential drug interactions

    Hosp Pharm

    (1998)
  • CA Jankel et al.

    Epidemiology of drug-drug interactions as a cause of hospital admissions

    Drug Saf

    (1993)
  • O Schneitman-McIntire et al.

    Medication misadventures resulting in emergency department visits at an HMO medical center

    Am J Health Syst Pharm

    (1996)
  • RA Hamilton et al.

    Frequency of hospitalization after exposure to known drug-drug interactions in a Medicaid population

    Pharmacotherapy

    (1998)
  • LE Shapiro et al.

    Pharmacokinetic mechanisms of drug-drug and drug-food interactions in dermatology

    Curr Probl Dermatol

    (1997)
  • W Andersen et al.

    Adverse drug interactions clinically important for the dermatologist

    Arch Dermatol

    (1995)
  • JQ Del Rosso

    Clinically significant drug interactions: recognition and understanding of common mechanisms

    Curr Pract Med

    (1998)
  • J Hoey

    Postmarketing drug surveillance: what it would take to make it work

    CMAJ

    (2001)
  • P Bonnabry et al.

    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

    (2001)
  • G Anastasio et al.

    Drug interactions: keeping it straight

    Am Fam Physician

    (1997)
  • M Morii et al.

    Impairment of mycophenolate mofetil absorption by iron ion

    Clin Pharmacol Ther

    (2000)
  • GP Bodey

    Azole antifungal drugs

    Clin Infect Dis

    (1992)
  • PD Hansten

    Drug interactions

    Drug Interactions Newsletter

    (1996)
  • Drug interactions

    The Medical Letter

    (1999)
  • R Preiss

    P-glycoprotein and related transporters

    Int J Clin Pharmacol Ther

    (1998)
  • KS Lown et al.

    Role of intestinal p-glycoprotein (mdr1) in interpatient variation in the oral bioavailabity of cyclosporine

    Clin Pharmacol Ther

    (1997)
  • CN Burkhart

    Ivermectin: an assessment of its pharmacology, microbiology and safety

    Vet Hum Toxicol

    (2000)
  • PD Hansten

    Drug interactions

    Drug Interactions Newsletter

    (1996)
  • Watkins

    Drug metabolism by cytochromes 450 in the liver and small bowel

    Gastroenterol Clin North Am

    (1996)
  • FP Guengerich

    Human cytochrome P450 enzymes

  • S Rendic et al.

    Human cytochrome P450 enzymes

    Drug Metab Rev

    (1997)
  • Drug interactions

    The Medical Letter

    (1999)
  • N Ford et al.

    Clinically significant cytochrome P-450 drug interactions—a comment

    Pharmacotherapy

    (1998)
  • PA Thurmann et al.

    Influence of gender on the pharmacokinetics and pharmacodynamics of drugs

    Int J Clin Pharmacol Ther

    (1998)
  • M Kotlyar et al.

    Effects of obesity on the cytochrome P450 enzyme system

    Int J Clin Pharmacol

    (1999)
  • RJ Bertz et al.

    Use of in vivo and in vitro data to estimate the likelihood of metabolic pharmacokinetic interactions

    Clin Pharmacokinet

    (1997)
  • AK Daly

    Molecular basis of polymorphic drug metabolism

    J Mol Med

    (1995)
  • LW Wormhoudt et al.

    Genetic polymorphism of human N-acetyltransferase, cytochrome P450, glutathione-s-transferase and epoxide hydrolase enzymes: relevance to xenobiotic metabolism and toxicity

    Crit Rev Toxicol

    (1999)
  • LW Wormhoudt et al.

    Genetic polymorphism of human n-acetyltransferase, cytochrome P450, glutathione-S-transferase, and epoxied hydrolase enzymes: relevance to xenobiotic metabolism and toxicity

    Crit Rev Toxicol

    (2000)
  • M Butler et al.

    Determination of CYP1A2 and NAT2 phenotypes in human populations by analysis of caffeine urinary metabolites

    Pharmacogenetics

    (1992)
  • BL Lee et al.

    Altered patterns of drug metabolism in patients with acquired immunodeficiency syndrome

    Clin Pharmacol Ther

    (1993)
  • P Tugwell et al.

    Methotrexate in rheumatoid arthritis: indications, contraindications, efficacy and safety

    Ann Intern Med

    (1987)
  • BP Monahan et al.

    Torsades do pointes occurring in association with terfenadine use

    JAMA

    (1990)
  • Cited by (91)

    • Polymorphisms

      2020, Comprehensive Dermatologic Drug Therapy, Fourth Edition
    • Drug Interactions

      2020, Comprehensive Dermatologic Drug Therapy, Fourth Edition
    • The 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 Research
      Citation 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.

    • Influence of quercetin on amiodarone pharmacokinetics and biodistribution in rats

      2023, European Review for Medical and Pharmacological Sciences
    • Hydrocodone, Oxycodone, and Morphine Metabolism and Drug–Drug Interactions

      2023, Journal of Pharmacology and Experimental Therapeutics
    View all citing articles on Scopus

    Funding sources: None.

    ☆☆

    Disclosure: Dr Shear is a paid consultant for Roche, GlaxoSmithKline, Galderma, and Novartis.

    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.

    View full text