Differences In Drug Disposition Research Articles

Sex Differences in Drug Disposition

Physiological, hormonal, and genetic differences between males and females affect the prevalence, incidence, and severity of diseases and responses to therapy. Understanding these differences is important for designing safe and effective treatments. This paper summarizes sex differences that impact drug disposition and includes a general comparison of clinical pharmacology as it applies to men and women.

Understanding the Relative Roles of Pharmacogenetics and Ontogeny in Pediatric Drug Development and Regulatory Science

Understanding the dose-exposure-response relationship across the pediatric age spectrum from preterm and term newborns to infants, children, adolescents, and adults is a major challenge for clinicians, pharmaceutical companies, and regulatory agencies. Over the past 3 decades, clinical investigations of many drugs commonly used in pediatric therapeutics have provided valuable insights into age-associated differences in drug disposition and action. However, our understanding of the contribution of genetic variation to variability in drug disposition and response in children generally has lagged behind that of adults. This article proposes a systematic approach that can be used to assess the relative contributions of ontogeny and genetic variation for a given compound. Application of the strategy is illustrated using the current regulatory dilemma posed by the safety and effectiveness of over-the-counter cough and cold remedies as an example. The results of the analysis can be used to aid in the design of studies to yield maximally informative data in pediatric populations of different ages and developmental stages and thereby improve the efficiency of study design.

Species differences in the multiple-dose pharmacokinetics of the non-nucleoside reverse transcriptase inhibitor (NNRTI) UK-453,061 in animals and man: implications for safety considerations

The requirements for safe testing of pharmaceuticals in humans places substantial emphasis on the translation of safety testing performed in animals to man.The comparison of systemic exposure in animals and man has taken on increasing importance in this assessment, with the underlying assumption that plasma concentrations will elicit the same response in different species. This assumption may be flawed for a number of different reasons, one of which is differences in drug disposition between species leading to high doses required in animal species to yield equivalent systemic exposure to humans and consequent higher exposure to organs such as the intestine and liver.Hepatic clearance can vary substantially, particularly between rodents and man, resulting in vast differences in the dose–exposure relationship. A specific example of a non-nucleoside reverse transcriptase inhibitor, which causes substantial auto-induction in rodents, is used to illustrate this situation and the impact this has on the interpretation of safety extrapolation from animals to man.In such circumstances, it is important to recognize the impact of species differences in drug clearance and disposition and consider broader input in the assessment of clinical safety.

Cisplatin + irinotecan versus cisplatin + etoposide in extensive stage small cell lung cancer (E-SCLC): Final “common arm”: Comparative outcomes analysis of JCOG 9511 and SWOG 0124

8027 Background: S0124 was a large North American phase III trial (n=651) that failed to confirm a survival benefit for cisplatin/irinotecan over cisplatin/etoposide in patients with E-SCLC, contrary to the results of J9511, a phase III trial exclusively in Japanese patients (n=154). As S0124 and J9511 protocols used identical treatment regimens and similar eligibility criteria, we compared demographics, toxicity, and outcomes using patient-level data and a “common arm” analysis to explore potential reasons for the divergent results. Methods: In both trials, patients with documented E-SCLC and adequate end-organ function were randomized to receive either cisplatin 60 mg/m2 day 1 + irinotecan 60 mg/m2 days 1, 8, & 15 Q 4 weeks or cisplatin 80 mg/m2 day 1 + etoposide 100 mg/m2 days 1–3 Q 3 weeks. Demographics and outcomes data were compared among 805 patients enrolled in J9511 and S0124 receiving identical treatment using a logistic model adjusted for age, sex, and performance status. Results: Of 671 patients in S0124, 651 were eligible. Patient characteristics (J9511 & S0124, respectively): Mean age - 61 & 62 years; Male sex - 132 (86%) & 370 (57%), p<0.001; Performance status 0 - 19 (12%) & 211 (32%), p<0.001. Efficacy and toxicity comparisons are summarized below. Conclusions: Significant differences in patient demographics, toxicity, and efficacy exist between J9511 and S0124 populations. These results, relevant in the current era of clinical trials globalization, warrant 1) consideration of differential patient characteristics and outcomes amongst populations receiving identical therapy; 2) utilization of the “common arm” model in prospective trials; and 3) inclusion of pharmacogenomic correlates in cancer trials where ethnic/racial differences in drug disposition are expected. [Table: see text] [Table: see text]

Pharmacotherapeutics of epilepsy: use of lamotrigine and expectations for lamotrigine extended release

The goal in managing patients with epilepsy is complete seizure freedom. Pharmacotherapeutic management of epilepsy is complicated by multiple syndromes, inter-individual differences in drug sensitivities, inter-individual differences in drug disposition, and drug interactions. Most anti-epileptic drugs (AEDs) have a therapeutic window with only a 2- to 3-fold concentration range. Extended release formulations offer advantages over their immediate release counter parts with less fluctuation in the serum concentration vs time curve and improved compliance. However, missed doses are more likely to result in prolonged "sub-therapeutic serum concentrations". Best clinical outcome may sometimes require twice daily dosing of extended release formulations even though approved for once daily dosing, as this optimally balances pharmacokinetics against compliance. Lamotrigine (LTG) is a broad spectrum AED with efficacy in partial and generalized epilepsy syndromes and good tolerability. Its metabolism is affected by co-medications which may be inducing, neutral or inhibiting of hepatic glucuronidation. Furthermore, though the average half-life in monotherapy is about 24 hours, there is a large inter-individual variation that may, including the extremes, approach a range of 10-fold. LTG-XR is expected to decrease fluctuation of serum concentration in the presence of hepatic inducing or neutral drugs. However, optimal clinical benefit in some patients may require twice daily dosing when metabolism is rapid.

Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice

The National Institute on Aging's Interventions Testing Program was established to evaluate agents that are purported to increase lifespan and delay the appearance of age-related disease in genetically heterogeneous mice. Up to five compounds are added to the study each year and each compound is tested at three test sites (The Jackson Laboratory, University of Michigan, and University of Texas Health Science Center at San Antonio). Mice in the first cohort were exposed to one of four agents: aspirin, nitroflurbiprofen, 4-OH-alpha-phenyl-N-tert-butyl nitrone, or nordihydroguaiaretic acid (NDGA). Sample size was sufficient to detect a 10% difference in lifespan in either sex,with 80% power, using data from two of the three sites. Pooling data from all three sites, a log-rank test showed that both NDGA (p=0.0006) and aspirin (p=0.01) led to increased lifespan of male mice. Comparison of the proportion of live mice at the age of 90% mortality was used as a surrogate for measurement of maximum lifespan;neither NDGA (p=0.12) nor aspirin (p=0.16) had a significant effect in this test. Measures of blood levels of NDGA or aspirin and its salicylic acid metabolite suggest that the observed lack of effects of NDGA or aspirin on life span in females could be related to gender differences in drug disposition or metabolism. Further studies are warranted to find whether NDGA or aspirin, over a range of doses,might prove to postpone death and various age-related outcomes reproducibly in mice.

Differences in the pharmacokinetics of protease inhibitors between healthy volunteers and HIV-infected persons

Pharmacokinetic and drug-drug interaction studies are conducted in both healthy volunteers and the target population (HIV-infected patients), but there is little discussion of the potential for differences in drug disposition between the two groups. It is important to recognize that the pharmacokinetics of drugs may be altered in HIV-infected persons as compared with healthy individuals. The aim of this review is to highlight some of the important differences in drug handling between healthy volunteers and HIV-infected individuals, focusing on protease inhibitors. Studies aimed at characterizing disparities in pharmacokinetics between healthy volunteers and HIV patients are lacking. Data suggest that concentrations of some protease inhibitors are lower in HIV patients than in HIV-negative volunteers (atazanavir and tipranavir), but generally comparisons are made across studies and study centres, and so multiple variables, such as differences in food and study design, can influence findings. We have conducted an 'in-house' analysis, comparing atazanavir, lopinavir and saquinavir between HIV-infected patients and healthy volunteers enrolled in the same study centre with similar study designs. For atazanavir the current data are quite convincing that concentrations are lower in HIV-infected patients than in healthy individuals, but for others it is not so clear. The 'in-house' analyses for atazanavir, lopinavir and saquinavir attempted to address some of the difficulties with cross-study comparisons, but it should be noted that subject numbers were small. Physiological changes resulting from HIV disease can influence drug pharmacokinetics and the underlying mechanisms remain to be elucidated.

Obesity in Dose Calculation: A Mouse or an Elephant?

Obesity in Dose Calculation: A Mouse or an Elephant?

The influence of CYP2D6 phenotype on the clinical response of nebivolol in patients with essential hypertension

* The variability in drug metabolism has been recognized as an important factor in the occurrence of adverse effects or lack of therapeutic efficacy. * The metabolism of the third-generation beta(1)-receptor antagonist nebivolol has been shown to be highly dependent on cytochrome P450 2D6 enzymatic activity in preclinical studies. * This paper assesses the role of a cytochrome P450 2D6 gene defect on the antihypertensive response to nebivolol in a clinical setting. * Despite significant differences in drug disposition, the chronic administration of nebivolol produced similar efficacy and tolerability in hypertensive patients either characterized as poor or extensive metabolizers of the drug. * The study offers insight into the relative contribution of nebivolol enantiomers in systemic blood pressure control. Nebivolol is a beta(1)-adrenergic receptor antagonist with vasodilating properties used in the treatment of hypertension. It is administered as a racemic mixture (D- and L-nebivolol) and is highly metabolized by the cytochrome P-450 2D6 (CYP2D6). The purpose of this study was to determine the role of CYP2D6 phenotypes on the efficacy and tolerability of nebivolol during chronic administration to patients with essential hypertension. Two hundred and eighteen patients were genotyped and phenotyped for CYP2D6 activity, allowing to find and match 14 poor metabolizers (PMs) with 23 extensive metabolizers (EMs). Patients took rac-nebivolol 5 mg daily for 12 weeks. Blood pressure (BP), heart rate, adverse events, plasma levels of the two enantiomers D- and L-nebivolol and their corresponding hydroxymetabolites were assessed. The metabolic disposition of nebivolol was enantioselective and highly influenced by CYP2D6 phenotypes. Mean steady-state plasma concentrations of D- and L-nebivolol were 10- and 15-fold greater in PMs than in EMs, respectively (P < 0.0001). Despite these differences in the pharmacokinetics of nebivolol, EMs and PMs displayed similar BP responses. Mean reductions in sitting systolic and diastolic BPs were -11/-10 +/- 9/4 mmHg in EMs and -11/-9 +/- 10/5 mmHg in PMs. Side-effects were mild to moderate and not different between groups. Polymorphisms in the gene encoding CYP2D6 significantly influenced the metabolism of nebivolol, but not its antihypertensive efficacy and tolerability. The similar clinical response between EMs and PMs could be explained by the contribution of active hydroxylated metabolites of nebivolol to its antihypertensive actions in EMs.

Second Japan-SWOG common arm analysis of paclitaxel/carboplatin in advanced stage non-small cell lung cancer (NSCLC): A model for testing population-related pharmacogenomics

7050 Background: Whether results of clinical trials performed outside the United States (US) can be fully extrapolated to US populations remains in question due to potential differences in trial designs, study-specific criteria, patient demographics, and population-related pharmacogenomics. The first of these comparisons, FACS-S0003 has been presented (Gandara, PASCO, 2004). Here we present the second comparative analysis. Methods: We prospectively designed &amp; conducted 3 separate phase III trials in advanced NSCLC linked by a “common arm” with identical eligibility, staging, response &amp; toxicity criteria, to: 1) determine similarities &amp; differences in patient demographics &amp; outcomes in cooperative group trials in Japan (in this analysis, the Japan Multinational Trial Organization LC03) &amp; the US (SWOG 0003), 2) provide the basis for global standardization in clinical trials in NSCLC, and 3) facilitate regulatory changes needed for joint Japan-US studies. We performed a planned comparative analysis of the paclitaxel/carboplatin arms from LC03 &amp; S0003, which had identical doses and schedules of paclitaxel dose (225mg/m2) and carboplatin (AUC 6). Conclusions: 1) This common arm analysis, as in our prior FACS-S003 report, shows great similarities in patient demographics between the LC03 and S0003. 2) Variable toxicities may be due to population-related pharmacogenomics (increased neutropenia &amp; febrile neutropenia in LC03), and could be explained by polymorphisms in cytochrome P450 for paclitaxel metabolism (ongoing analysis). 3) Survival is increased in LC03. 4) Future joint Japan-US clinical trials should assess possible pharmacogenomic differences in drug disposition. [Table: see text] No significant financial relationships to disclose.

Association between multidrug resistance 1 ( MDR1) gene polymorphisms and therapeutic response to bromperidol in schizophrenic patients: A preliminary study

The drug-transporting P-glycoprotein transports drugs against a concentration gradient across the blood–brain barrier back into the plasma and thereby reduces the bioavailability in the brain. Polymorphisms in the MDR1 gene regulating P-glycoprotein expression can be associated with differences in drug disposition in the brain. The present study was therefore designed to examine whether the major polymorphisms of MDR1 gene, C3435T and G2677T/A are related to therapeutic response to neuroleptics in the treatment of schizophrenia. Subjects consisted of 31 acutely exacerbated schizophrenic inpatients treated with bromperidol (6–18 mg/day). Plasma drug concentrations were monitored and clinical symptoms were evaluated using the Brief Psychiatric Rating Scale (BPRS) before and 3 weeks after the treatment. The C3435T and G2677T/A genotypes were determined by a polymerase chain reaction method. Schizophrenic symptoms were allocated into 5 clusters: positive, excitement, cognitive, negative, and anxiety–depression symptoms. Patients were C/C in 12, C/T in 12 and T/T in 7 cases for C3435T genotype and G/G in 3, G/T or A in 17 and T or A/T or A in 11 cases for G2677T/A genotype. There were a tendency of difference, but not statistically different, in the percentage improvement or the improved scores of 5 sub-grouped symptoms after the 3-week treatment between C3435T genotypes and between G2677T/A genotypes. Multiple regression analyses including age, body weight, gender and drug concentration showed significant correlations between the percentage improvement and the improved scores of cognitive symptoms and C3435T genotypes. The present results suggest that the C3435T polymorphism is associated with some therapeutic response to bromperidol in schizophrenic patients, possibly by different drug concentration in the brain.

Impact of molecular profiling and cytogenetics in acute lymphoblastic leukemia

"Impact of molecular profiling and cytogenetics in acute lymphoblastic leukemia." Hematology, 10(sup1), pp. 176–177

Drug Metabolism and Variability among Patients in Drug Response

Differences in drug responsiveness are common, often leading to challenges in optimizing the dosage regimen for a particular patient. Recent advances provide a rational framework for understanding many interpatient differences in drug disposition and their clinical consequences. This article focuses on the cytochrome P-450 enzymes, a superfamily of microsomal drug-metabolizing enzymes that play an important role in oxidative drug metabolism.

Handbook of Analytical Separations, Vol. 5: Drug Monitoring and Clinical Chemistry

This volume is the fifth in a series, which has previously described methodology used for qualitative and quantitative analysis in the areas of drug synthesis and purification, forensic science, environmental analysis and bioanalytical separations. The book is an attempt to give a comprehensive account of the current state of the field of therapeutic drug monitoring and contains 13 chapters, each contributed by expert authors and extensively referenced. The first four chapters concentrate on the practical aspects of analysis, discussing methods for isolating drugs from biological fluids and their subsequent measurement. HPLC with ultraviolet, fluorescence and mass spectrometric detection and gas chromatography, also coupled with mass spectrometry, are now commonly used for drug analysis and all are discussed in detail. The analysis of chiral drugs is also examined, as is the use of capillary electrophoresis and immunoassay. A vital aspect of any analytical procedure is validation of the method and a chapter is devoted to ways of ensuring that drug measurements are accurate and reproducible. This is of great importance, especially where drugs have narrow therapeutic ranges and high drug levels are associated with toxicity. Measurement of drug concentration in blood serum is by far the commonest form of therapeutic drug monitoring and the therapeutic range of a drug is the serum concentration associated with maximum desired therapeutic effect and minimum toxicity. Consequently, the lower and upper limits of the therapeutic range of a drug can be difficult to define and may also differ markedly between individuals. Pharmacokinetic models can be extremely useful in addressing these problems and a chapter is included discussing their application in the individualization of drug dosage regimens. Further chapters discuss the use of therapeutic drug monitoring in controlling the efficacy of drugs for cancer chemotherapy, antibiotic therapy, epilepsy, depression, psychosis and immunosuppression. Individuals respond to medications differently and these differences in drug disposition are often due to genetic variation encoding the activity of drug-metabolizing enzymes such as the cytochrome P450 family. Consequently, various technologies are now used to genotype and phenotype individuals for polymorphisms in drug-metabolizing enzyme activity. Two chapters are included on this subject, one discussing the methodologies available to detect the polymorphisms, and the other describing clinically relevant applications to specific drugs. This volume is a very well constructed overview of the field of therapeutic drug monitoring and includes chapters on all relevant areas. Every chapter is well written and comprehensively referenced so that the reader can readily access the primary literature. With the detail that is included and the range of topics covered, it is a volume that is highly recommended to both experts in the field and the casual reader.

Japan-SWOG common arm analysis of paclitaxel/carboplatin in advanced stage non-small cell lung cancer (NSCLC): A model for prospective comparison of cooperative group trials

7007 Background: Whether results of clinical trials performed outside the United States (US) can be fully extrapolated to US populations remains in question due to potential differences in trial designs, study-specific criteria, patient demographics, and population-related pharmacogenomics. Methods: We prospectively designed & conducted separate phase III trials in advanced NSCLC linked by a “common arm” with identical eligibility, staging, response & toxicity criteria, to: 1) determine similarities & differences in patient demographics & outcomes in cooperative group trials in Japan (Four Arm Cooperative Study or FACS) & the US (SWOG 0003), 2) provide the basis for global standardization in clinical trials in NSCLC, and 3) facilitate regulatory changes needed for joint Japan-US studies sponsored by the US National Cancer Institute (NCI). We performed a planned comparative analysis of the paclitaxel/carboplatin arms from FACS & S0003, identical except for paclitaxel dose of 200mg/m2 in FACS, 225mg/m2 in S0003, based on the MTD from separate phase I studies in Japan and the US. Carboplatin: AUC 6 in both. Results: Conclusions: 1) This common arm analysis shows great similarities in patient demographics between the FACS and S0003. 2) Variable toxicities may be due to differences in cumulative paclitaxel dose (neuropathy) and/or population-related pharmacogenomics (increased neutropenia & febrile neutropenia in FACS despite lower paclitaxel dose). 3) Survival is increased in FACS. 4) Future joint Japan-US clinical trials should consider possible pharmacogenomic differences in drug disposition. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb

Challenges in Current Drug Delivery from the Potential Application of Pharmacogenomics and Personalized Medicine in Clinical Practice

The recent technological achievements in biotechnology and recombinant DNA technology have provided multiple new methods, molecular targets, and DNA-based diagnostics to pharmaceutical research that can be utilized in assays for screening and developing potential biotechnology-based drugs, as well as in biomedicine, health and pharmaceutical care. Furthermore, such advances opened up new opportunities by applying genetic information data in pharmacotherapy and drug delivery, thus ensuring better drug efficacy and safety in clinical practice. Now the concepts of personalized medicine and pharmacogenomics are likely improving the area of pharmacodynamics and pharmacokinetics, since they favor differentiation of the conventional clinical diagnosis and drug selection into separate molecular subtypes of individuals belonging within a group of patients suffering from the same disease. Genetic polymorphisms have already been detected and analyzed in genes encoding drug-metabolizing enzymes, transporters as well as targets (e.g. receptors). The potential of applying genotyping and haplotyping analysis in future pharmaceutical care could eventually lead to pharmacotyping, i.e. individualized drug delivery profiling based on genetic-bioinformatic data in routine patient care. However, the steps towards this direction of drug delivery in clinical practice still have a long way to go to be fully achieved; until then, the critical evaluation of all available clinical data including pharmacodynamic, pharmacokinetic and genomic must be assessed for ensuring drug efficacy and safety. In this way, there has been great progress in elucidating genetic determinants contributing to the observed interindividual differences in drug disposition and effects, thus implementing current drug delivery with molecular genetics and diagnostics.

Genetic Polymorphism of Organic Anion and Cation Transporters: Pharmacokinetic and Pharmacodynamic Consequences in Pharmacotherapy

It has been suggested that genetic polymorphisms in drug transporters as well as drug-metabolizing enzymes are associated with interindividual differences in drug disposition, efficacy, and toxicity and in disease. Organic anion and cation transporters are expressed in the selective or multiple tissues such as small intestine, liver and kidney, and mediate the transport of many clinically useful drugs. Polymorphisms of drug transporter genes have recently been identified and demonstrated to have functional significance for transporter activity and expression. For example, genetic variants in the OATP-C (SLC21A6) gene are associated with alterations in pravastatin and rifampin uptake into liver. In addition, homozygotes for OCTN2 (SLC22A5) mutant alleles cause systemic carnitine deficiency because of a disruption of carnitine reabsorption in the kidney. Since a growing number of preclinical and clinical studies have demonstrated that the polymorphisms of various drug transporter genes may be responsible for overall outcomes of pharmacokinetics and pharmacotherapy of certain drugs, further understanding of the physiology and biochemistry of drug transporters with respect to genetic variations will be important to establish individualized pharmacotherapy with clinically used drugs. Keywords: anion and cation transporters, genetic polymorphisms, clinically useful drugs, pharmacokinetics, pharmacodynamics

Optimizing immunomodulator therapy for inflammatory bowel disease.

6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) remain the mainstay of immunomodulator therapy for the maintenance of steroid-free remission in patients with inflammatory bowel disease (IBD). Traditional dosing strategies for initiation of thiopurines are often based on weight or empirically chosen. Dosing based on an understanding of an inherited difference in drug disposition and metabolism may provide a safer alternative. The thiopurine methyltransferase (TPMT) enzyme plays a pivotal role in the metabolism of 6-MP and AZA and is critical to the determination of thiopurine toxicity. The therapeutic benefits of thiopurines correlate best with concentration of the active 6-thioguanine (6-TGN) metabolites. Reports suggest that therapeutic response can be maximized when patients achieve therapeutic 6-TGN levels. Pharmacogenetic dosing based on TPMT and pharmacokinetic dosing based on 6-TGN levels may offer a safety and efficacy advantage over traditional dosing strategies and provide a novel mechanism for optimizing immunomodulator therapy in IBD.

Cancer Pharmacogenomics: SNPs, Chips, and the Individual Patient

There is great heterogeneity in a patient's response to medications, often requiring empirical strategies to define the appropriate drug therapy for each patient. Pharmacogenomics aims to elucidate further the inherited nature of interindividual differences in drug disposition and effects, with the ultimate goal of providing a stronger scientific basis for selecting the optimal drug therapy and dosage for each patient. These genetic insights should also lead to mechanism-based approaches to the discovery and development of new medications. Genetic polymorphisms in drug metabolizing enzymes, transporters, receptors, and other drug targets have been linked to interindividual differences in the efficacy and toxicity of many medications. For example, polymorphism in thiopurine methyltransferase (TPMT) results in altered degradation of the commonly prescribed agent 6-mercaptopurine This genetic variant has significant clinical implications because patients with functionally relevant homozygous mutations in the TPMT gene experience extreme or fatal toxicity after administration of normal doses of 6-MP. In addition, patients heterozygous for mutations in TPMT require slight dosage reduction of 6-MP and experience a greater degree of systemic toxicity from the agent. This and other examples of genetic polymorphism relevant to the treatment of cancer are highlighted to illustrate the promise and pitfalls of the exciting area of cancer therapeutics, with the potential of providing a stronger scientific basis to optimize drug therapy on the basis of each patient's genetic constitution.

Genetic basis of drug metabolism.

The application of pharmacogenetics in identifying single nucleotide polymorphisms (SNPs) in DNA sequences that cause clinically significant alterations in drug-metabolizing enzyme activities is discussed. Recent advances in pharmacogenomic research have begun to elucidate the inherited nature of interindividual differences in drug-induced adverse reactions, toxicity, and therapeutic responses. In one particular area of study, variations in DNA sequences (i.e., genetic polymorphisms) explain some of the variability in drug-metabolizing enzyme activities which contribute to alterations in drug clearance and impact patients' response to drug therapy. Historical and current examples of several extensively studied SNPs include the genes encoding for glucose-6-phosphate dehydrogenase, N-acetyltransferase, and the superfamily of cytochrome P-450 (CYP) isoenzymes. Because CYP isoenzymes metabolize a large number of structurally diverse drugs and chemicals, most of the variant genotypes of the CYP2D6, CYP2C9, CYP2C19, and CYP3A families have been identified and studied. Individuals with aberrant genes for these enzymes may experience diminished efficacy or increased toxicity in response to certain drugs because of the different levels of activities associated with variant genotypes. The frequency of variant alleles for drug-metabolizing enzymes often differs among ethnic groups. Continued research in pharmacogenetics will further our understanding in interindividual differences in drug disposition. The application of this knowledge will ultimately help individualize drug dosing and drug therapy selection, predict toxicity or therapeutic failure, and improve clinical outcomes. Pharmacogenetics has elucidated the genetic basis for interindividual variability in drug response and will continue to play a key role in defining strategies to optimize drug therapy.