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Warfarin is the most commonly prescribed oral anticoagulant worldwide despite its narrow therapeutic index and the notorious inter- and intra-individual variability in dose required for the target clinical effect. Pharmacogenetic polymorphisms are major determinants of warfarin pharmacokinetic and dynamics and included in several warfarin dosing algorithms. This review focuses on warfarin pharmacogenomics in sub-Saharan peoples, African Americans and admixed Brazilians. These 'Black' populations differ in several aspects, notably their extent of recent admixture with Europeans, a factor which impacts on the frequency distribution of pharmacogenomic polymorphisms relevant to warfarin dose requirement for the target clinical effect. Whereas a small number of polymorphisms in VKORC1 (3673G > A, rs9923231), CYP2C9 (alleles *2 and *3, rs1799853 and rs1057910, respectively) and arguably CYP4F2 (rs2108622), may capture most of the pharmacogenomic influence on warfarin dose variance in White populations, additional polymorphisms in these, and in other, genes (e.g. CALU rs339097) increase the predictive power of pharmacogenetic warfarin dosing algorithms in the Black populations examined. A personalized strategy for initiation of warfarin therapy, allowing for improved safety and cost-effectiveness for populations of African descent must take into account their pharmacogenomic diversity, as well as socio-economical, cultural and medical factors. Accounting for this heterogeneity in algorithms that are 'friendly' enough to be adopted by warfarin prescribers worldwide requires gathering information from trials at different population levels, but demands also a critical appraisal of racial/ethnic labels that are commonly used in the clinical pharmacology literature but do not accurately reflect genetic ancestry and population diversity., (© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.)

Aim: Genetic variants of the enzyme that metabolizes warfarin, cytochrome P-450 2C9 (CYP2C9) and of a key pharmacologic target of vitamin K antagonists, vitamin K epoxide reductase (VKORC1), contribute to differences in patients' responses to coumarin derivatives. The role of these variants in fluindione response is unknown. Our aim was to assess whether genetic factors contribute to the variability in the response to fluindione., Methods: Four hundred sixty-five patients with a venous thromboembolic event treated by fluindione for at least 3 months with a target international normalized ratio (INR) of 2.0 to 3.0 were studied. VKORC1, CYP2C9, CYP4F2 and EPHX1 genotypes were assessed. INR checks, fluindione doses and bleeding events were collected., Results: VKORC1 genotype had a significant impact on early anticoagulation (INR value ≥2 after the first two intakes) (P < 0.0001), on the time required to reach a first INR within the therapeutic range (P < 0.0001) and on the time to obtain a first INR value > 4 (P= 0.0002). The average daily dose of fluindione during the first period of stability was significantly associated with the VKORC1 genotype: 19.8 mg (±5.5) for VKORC1 CC, 14.7mg (±6.2) for VKORC1 CT and 8.2mg (±2.5) for VKORC1 TT (P < 0.0001). CYP2C9, CYP4F2 and EPHX1 genotypes did not significantly influence the response to fluindione., Conclusions: VKORC1 genotype strongly affected anticoagulation induced by fluindione whereas CYP2C9, CYP4F2 and EPHX1 genotypes seemed less determining., (© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.)

Clopidogrel is a pro-drug which is converted to an active metabolite that selectively blocks ADP-dependent platelet activation and aggregation. The main enzyme responsible for activating clopidogrel is the cytochrome P450 (CYP) isoenzyme CYP2C19, which is polymorphic. There is a growing body of literature showing that carriers of variant CYP2C19 alleles have impaired ability to metabolize clopidogrel (i.e. poor metabolizers), which is associated with decreased inhibition of platelet aggregation and increased cardiovascular risk. Some proton pump inhibitors are also metabolized by the CYP2C19 enzyme and often given together with clopidogrel to reduce gastrointestinal side effects. In particular, omeprazole has been shown to inhibit the CYP-mediated metabolism of clopidogrel, and some studies have shown that the combination was associated with a higher incidence of cardiovascular adverse reactions than clopidogrel given alone. However, a recent randomized controlled trial demonstrated no significant difference in adverse cardiovascular events for patients on the combination of clopidogrel and omeprazole compared with clopidogrel alone. This current review aims to summarize the role of pharmacogenetics and drug interactions in determining variability in response to clopidogrel., (© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.)

What Is Already Known About This Subject: Variants in the CYP2C9 (i.e. *2 and *3) and VKORC1 (i.e. 1173C/T or -1639G/A) genes have been shown to influence warfarin dose requirements. However, these factors seem to explain less of the dose variability in African Americans who have a lower prevalence of the CYP2C9*2 and *3 and VKORC1 1173T alleles., What This Study Adds: In African Americans, the VKORC1 rs17886199 variant was statistically significantly associated with log-transformed warfarin maintenance dose, independent of the influence of VKORC1 1173C>T and CYP2C9*2 and *3. However, replication of our finding is needed to confirm the association of rs1786199 SNP in African Americans, since Limdi et al.[3] did not examine the effect of this SNP because the prevalence of the rs1786199 A-allele was too low., Aims: To raise hypotheses with regards to whether genetic variants in the VKORC1, CYP2C9, EPHX1, GGCX and ALB genes might influence warfarin dose in African Americans and Caucasians, independent of the effects of the VKORC1 1173C>T and CYP2C9*2 and *3 variants., Methods: From a prospective cohort study, we obtained additional DNA on 36 Caucasian and 22 African American warfarin users who reached maintenance dose and genotyped them for tagSNPs (r2<0.8) in VKORC1, EPHX1, GGCX and ALB genes, and one exonic CYP2C9 SNP. Linear regression models were fitted to estimate the relationship (P value) between log-transformed maintenance dose and each SNP and the amount of the warfarin dose variability accounted for by each SNP (partial R2)., Results: In African Americans, the VKORC1 rs17886199 A-allele was associated with a lower dose (GG=46.3 mg and GA=25.6 mg; P=0.002), independent of the VKORC1 1173C>T and CYP2C9*2 and *3 variants. Even after applying Bonferroni correction, the P value would still be considered statistically significant. The VKORC1 rs17886199 variant was not found in Caucasians. In Caucasians, the EPHX1 rs1051741 T-allele was associated with a lower dose (CC=41.3 mg and CT=30.0 mg; P=0.04). The latter was no longer statistically significant after applying Bonferroni correction., Conclusions: Our pilot study suggests that the VKORC1 rs17886199 variant could influence warfarin maintenance dose among African Americans, even after accounting for the influence of the VKORC1 1173C>T variant. Future studies with a larger sample size will be needed to confirm our findings.

Aims: Although in vitro studies indicate that oxazepam is an isoform-selective substrate probe for UDP-glucuronosyltransferase 2B15, the utility of this drug as an in vivo probe is uncertain. The main aim of this study was to determine whether common missense polymorphisms in the UGT2B15 gene (D85Y and K523T) are associated with altered oxazepam pharmacokinetics and pharmacodynamics. We also determined the possible influence of a common deletion polymorphism in the gene encoding UGT2B17, which shows substantial substrate specificity overlap with UGT2B15., Methods: Thirty healthy male subjects were administered 15 mg of oxazepam by mouth followed by plasma oxazepam concentration monitoring for 36 h, and pharmacodynamic testing for 8 h. Genotypes were determined by genomic polymerase chain reaction and commercial 5'-nuclease assays., Results: Allele frequencies for D85Y, K523T, UGT2B17del were 47%, 23% and 19%, respectively. Median oxazepam apparent oral clearance was significantly lower in 85YY subjects (1.62 ml min(-1) kg(-1)) compared with 85DD subjects (3.35 ml min(-1) kg(-1); P= 0.003, Student-Newman-Keuls test), whereas 85DY subjects were intermediate (2.34 ml min(-1) kg(-1); P= 0.018 vs. 85DD, P= 0.034 vs. 85YY). Regression analysis indicated that UGT2B15 D85Y genotype accounted for 34% of interindividual variability. However, neither UGT2B15 K523T nor UGT2B17del was associated with altered oxazepam disposition. Furthermore, no differences in pharmacodynamic measures, including quantitative electroencephalography, digit-symbol substitution test, self- or observer-rated visual analogue scales, could be demonstrated for any of the polymorphisms evaluated., Conclusions: These results identify UGT2B15 D85Y as a major determinant of oxazepam clearance, and indicate that oxazepam may be useful as an in vivo probe for glucuronidation by UGT2B15.

Aim: To study the effect of the CYP2D6*4 polymorphism on serum sodium concentration in users of antidepressants [selective serotonin reuptake inhibitors and tricyclic antidepressants (TCAs)]., Methods: In this population-based cohort study, all subjects in the Rotterdam Study were included who used an antidepressant at baseline and from whom a blood sample was available in which CYP2D6 genotype and serum sodium concentration could be determined (n= 76). Multivariate linear regression was used to study the association between CYP2D6*4 and serum sodium concentration., Results: CYP2D6 poor metabolizers (PMs) (*4/*4) had a significantly lower mean serum sodium concentration in comparison with CYP2D6 extensive metabolizers (EMs) (*1/*1) [difference -3.9 mmol l(-1); 95% confidence interval (CI) -0.86, -7.03; P= 0.013]. In CYP2D6*4 heterozygotes (*1/*4) serum sodium concentration was 1.7 mmol l(-1) (95% CI -3.48, 0.18) lower compared with CYP2D6 EMs, but this difference was not statistically significant (P= 0.077)., Conclusions: The serum sodium concentration in PMs was lower in users of an antidepressant, especially in TCA users. Therefore CYP2D6 PMs might be at increased risk of developing symptoms of hyponatraemia.

Aims: The aim of this study was to explore the impact of UCP2 and ADRB3 genetic polymorphisms on the therapeutic efficacy of rosiglitazone in Chinese Type 2 diabetes (T2DM) patients., Methods: A total of 199 T2DM patients and 155 healthy volunteers were enrolled to identify UCP2 -866 G/A genotypes, and 273 T2DM patients and 166 controls were genotyped for Trp64Arg of ADRB3 by polymerase chain reaction-restriction fragment length polymorphism assay. Nine patients with GG genotype and 27 with GA+AA genotype of UCP2 -866 G/A, 11 with Trp64Trp genotype and 25 with Trp64Arg genotype of ADRB3 received oral rosiglitazone as a single-agent therapy (4 mg day(-1)) for 12 weeks. Serum fasting plasma glucose, postprandial plasma glucose, glycated haemoglobin (HbA(1c)), fasting serum insulin, postprandial serum insulin (PINS), triglycerol (TG), cholesterol, homeostasis model assessment for insulin resistance, leptin and adiponectin in all T2DM patients were determined before and after rosiglitazone treatment., Results: There were no differences in allele frequency of either ADRB3 Trp64Arg or UCP2 -866 G/A between T2DM patients and control subjects. The A allele carriers of UCP2 in the T2DM patients had significantly lower PINS (61.5 +/- 34.3 vs. 41.6 +/- 28.7 mU l(-1), P < 0.01) (37.57, 59.16 vs. 34.82, 49.39) and low-density lipoprotein (LDL)-cholesterol compared with GG genotypes (3.4 +/- 1.1 vs. 2.7 +/- 1.1 mmol l(-1), P < 0.05) (2.64, 3.52 vs. 2.66, 3.15). After rosiglitazone treatment for 12 consecutive weeks, we found that A allele carriers of UCP2 in the T2DM patients had smaller attenuated PINS (-3.82 +/- 13.2 vs.-42.1 +/- 30.7 mU l(-1), P < 0.01) (9.45, 51.31 vs. 0.48, 11.88) and greater attenuated HbA(1c) (-1.85 +/- 1.62 vs.-0.61 +/- 0.80, P < 0.05) (0.14, 1.37 vs. 1.10, 2.38) compared with GG genotypes, and ADRB3 Trp64Arg had greater attenuated serum TG (-3.88 +/- 2.77 vs.-0.24 +/- 1.16 mmol l(-1), P < 0.05) (-0.19, 2.74 vs. 1.19, 1.45) and smaller attenuated LDL-cholesterol (1.08 +/- 1.36 vs.-0.36 +/- 0.99, P < 0.01) (-1.26, 0.78 vs.-1.26, 0.79) as well as reduced enhanced adiponectin (1.57 +/- 1.10 vs. 3.15 +/- 2.12 mmol l(-1), P < 0.05) (1.68, 4.08 vs.-9.18, 11.40) compared with ADRB3 Trp64Trp., Conclusion: UCP2 -866 G/A and ADRB3 Trp64Arg polymorphisms are associated with the therapeutic efficacy of multiple-dose rosiglitazone in Chinese T2DM patients.

Aims: A number of drugs are substrates or inhibitors of the efflux transporter breast cancer resistance protein (BCRP; ABCG2), which can limit systemic exposure by reducing absorption and/or increasing biliary elimination. The identification of a BCRP-selective clinical probe drug would provide a useful tool to understand the effect of genetic polymorphisms and transporter-based drug interactions on drug pharmacokinetics. The aim of this study was to assess the utility of nitrofurantoin as a clinical probe substrate for BCRP activity by evaluating the impact of genetic variation on nitrofurantoin pharmacokinetics., Methods: Nitrofurantoin pharmacokinetics were studied in an open-label, single-oral dose (100 mg) study in 36 male Chinese subjects who were pre-screened for ABCG2 421 CC, CA and AA genotypes (n = 12 each). Plasma and urine concentrations of nitrofurantoin were determined by LC/MS/MS and LC/UV respectively. anova was used to compare pharmacokinetic parameters among genotypes., Results: There were no significant differences in nitrofurantoin pharmacokinetics among the genotypic cohorts. The geometric mean nitrofurantoin plasma AUC((0-infinity)) (95% confidence interval) values were 2.21 (2.00, 2.45), 2.42 (2.11, 2.78) and 2.32 (1.99, 2.70) microg h ml(-1) and half-life values were 0.79 (0.59, 1.0), 0.76 (0.64, 0.89) and 0.72 (0.62, 0.84) h for ABCG2 421 genotypes CC, CA and AA, respectively. The percentage of dose excreted unchanged in the urine was 43, 44 and 39%, respectively., Conclusions: The ABCG2 C421A polymorphism had no effect on nitrofurantoin plasma and urine pharmacokinetic parameters in healthy Chinese subjects. These results indicate that nitrofurantoin is not a suitable clinical probe substrate for assessing BCRP activity.

Aims: The aim was to perform a systematic review of all candidate gene association studies in aspirin resistance., Methods: Electronic databases were searched up until 1 December 2007 for all studies investigating any candidate gene for aspirin resistance in humans. Aspirin resistance was required to have been measured by a standardized laboratory technique to be included in the analysis., Results: Within 31 studies, 50 polymorphisms in 11 genes were investigated in 2834 subjects. The PlA1/A2 polymorphism in the GPIIIa platelet receptor was the most frequently investigated, with 19 studies in 1389 subjects. The PlA1/A2 variant was significantly associated with aspirin resistance when measured in healthy subjects [odds ratio (OR) 2.36, 95% confidence interval (CI) 1.24, 4.49; P = 0.009]. Combining genetic data from all studies (comprising both healthy subjects and those with cardiovascular disease) reduced the observed effect size (OR 1.14, 95% CI 0.84, 1.54; P = 0.40). Moreover, the observed effect of PlA1/A2 genotype varied depending on the methodology used for determining aspirin sensitivity/resistance. No significant association was found with aspirin resistance in four other investigated polymorphisms in the COX-1, GPla, P2Y1 or P2Y12 genes., Conclusions: Our data support a genetic association between the PlA1/A2 molecular variant and aspirin resistance in healthy subjects, with the effect diminishing in the presence of cardiovascular disease. The laboratory methodology used influences the detection of aspirin resistance. However, as heterogeneity was significant and our results are based on a limited number of studies, further studies are required to confirm our findings.

What Is Already Known About This Subject: * Most antidepressants are metabolized by CYP2D6. The variant allele CYP2D6*4 is the main polymorphism resulting in reduced enzyme activity in Caucasians. * Reduced enzyme activity potentially leads to increased toxicity of antidepressants, but the relevance of genotyping for clinical practice is unclear. Most clinical studies suffer from small numbers of patients., What This Study Adds: * This large population-based cohort study in 1198 elderly Dutch patients examines the influence of the CYP2D6*4 polymorphism on intolerability of antidepressants. * The risk of switching to another antidepressant in tricyclic antidepressant users is higher in poor metabolizers (PMs), but not in SSRI users. PMs require a lower maintenance dose of antidepressants compared with extensive metabolizers (EMs). * Antidepressants were initiated in a relatively low dose, with gradual dose increments thereafter, reducing the risk of adverse drug reactions. Therefore, the question remains whether genotyping prior to the start of antidepressant therapy contributes substantially to the optimization of pharmacotherapy., Aims: To study the effect of CYP2D6*4 on antidepressant dose, switching and discontinuation of therapy., Methods: The study consisted of all subjects in the Rotterdam Study, who received a first antidepressant prescription between April 1st 1991 and July 1st 2005 and for whom data on CYP2D6 genotype were available. Binary logistic regression was performed to study the association between CYP2D6*4 and switching to any other antidepressant or discontinuation of therapy within 45 days. The difference in mean antidepressant dose was compared between CYP2D6 genotypes using t-tests and repeated measurements analyses., Results: In users of tricyclic antidepressants (TCAs) the risk of switching to another antidepressant was significantly higher in poor metabolizers (PMs:*4/*4) compared with extensive metabolizers (EMs:*1/*1), with an adjusted OR of 5.77 (95% CI 1.59, 21.03; P = 0.01). In SSRI users there was no significant difference (OR 0.91; 95% CI 0.20, 4.15; P = 0.90). Heterozygous patients did not have an increased risk of switching in both TCA and SSRI users. The mean TCA dose was significantly lower in PMs than in EMs at the third and fourth prescription (difference 0.11 DDD, P = 0.03). In SSRI users the difference in mean dose between PMs and EMs was significant at the third prescription (0.17 DDD; P = 0.02)., Conclusions: The risk of switching to another antidepressant in TCA users is higher in PMs than in EMs. The maintenance doses of antidepressants were significantly lower in PMs. However, the question whether genotyping prior to the start of antidepressant therapy contributes substantially to the optimization of pharmacotherapy, requires further study.