Genetic polymorphisms of cytochrome P450 enzymes 2C9 and 2C19 in a healthy Iranian population

1. The genetically polymorphic cytochrome P450 enzymes 2C9 (CYP2C9) and 2C19 (CYP2C19) are involved in the metabolism and elimination of a number of widely used drugs. The polymorphisms give rise to substantial interindividual and interethnic variability in drug excretion rates and final serum concentrations. For this reason, therapeutic responses and adverse drug reactions may vary from one person to another. In the present study we determined CYP2C9 and CYP2C19 genotypes in a random Iranian population to compare allele frequencies with previous findings in other ethnic groups. 2. Allelic variants of CYP2C9 (*1/*2/*3) and CYP2C19 (*1/*2/*3) were determined in 200 unrelated healthy Iranian volunteers by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays. 3. Fifteen subjects (7.5) were homozygous for the CYP2C9*2 allele, whereas 21 individuals (10.5) were heterozygous for this allele and 164 subjects (82) had the wild-type allele (CYP2C9*1). No CYP2C9*3 was detected in the population sampled. Six subjects (3) were homozygous for CYP2C19*2, whereas 44 individuals (22) were heterozygous for this allele. In the remaining subjects (75), no CYP2C19*2 was found. In addition, no CYP2C19*3 was detected in the population sampled. 4. Based on our data, the frequency of the CYP2C9*2 allelic variant in Iranians is similar to that in other Caucasian populations; however, the frequency of the CYP2C9*3 allele differed significantly (P 0.05). © 2007 Blackwell Publishing Asia Pty Ltd

Genotype and allele frequencies of N-acetyltransferase 2 and glutathione S-transferase in the Iranian population

1. Xenobiotic-metabolizing enzymes constitute an important line of defence against a variety of carcinogens. Many are polymorphic, constituting the basis for the wide interindividual variation in metabolic capacity and possibly a source of variation in the susceptibility to chemical-induced carcinogenesis. The aim of the present study was to determine the frequencies of important allelic variants in the N-acetyltransferase 2 (NAT2) and glutathione S-transferase (GST) genes in the Iranian population and compare them with frequencies in other ethnic populations. 2. Genotyping was performed in a total of 229 unrelated healthy subjects (119 men, 110 women) for NAT2 and 170 unrelated healthy subjects (89 men, 81 women) for GST from the general Tehran population. A combination of polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) was applied for typing of NAT2 polymorphisms. Detection of GSTM1 and GSTT1 null alleles was performed simultaneously using a multiplex PCR assay. 3. The frequencies of specific NAT2 alleles were 0.299, 0.314, 0.380, 0.007 and 0.000 for *4 (wild-type), *5 (C481T, M1), *6 (G590A, M2), *7 (G857A, M3) and *14 (G191A, M4), respectively. The most prevalent genotypes were NAT2 *5/*6 (29.70) and *4/*6 (21.40). The GSTM1- and GSTT1-null alleles were detected in 44.7 and 21.2 of subjects, respectively. 4. We found that Iranians resemble Indians with regard to allelic frequencies of the tested variants of NAT2. The predominance of slow (49.36) and intermediate (41.47) acetylation status compared with wild-type rapid acetylation status (9.17) in the study group suggests the significant prevalence of the slow acetylator (SA) phenotypes in the Iranian population. Our data confirmed that Iranians are similar to other Caucasian populations in the frequency of both GSTM1- and GSTT1-null alleles. © 2007 The Authors

Population pharmacokinetics of S(−)-carvedilol in healthy volunteers after administration of the immediate-release (IR) and the new controlled-release (CR) dosage forms of the racemate

Carvedilol is a β1-, β1-, and α1-adrenoreceptor blocker indicated for treatment of hypertension and mild-tosevere congestive heart failure. The objective of this study was to develop and evaluate a single population model that describesS(−)-carvedilol pharmacokinetics from both the immediate-release (IR) and the new controlled-release dosage forms of the racemate. Carvedilol IR data (1270 measurements) were obtained from 2 open-label studies (50 mg/25 mg Q12 hours for 2 doses). Carvedilol CR data (2058 measurements) were obtained from an open-label, nonrandomized, dose-rising (10, 20, 40, and 80 mg), 4-period balanced crossover study. All data were simultaneously analyzed using NONMEM V. Leverage analysis and internal evaluations were conducted for the final model. A 2-compartment model with first-order absorption and elimination provided the best fit. The model included different absorption rates (KAs) for the CR and IR morning (IRAM) and evening (IRPM) doses; incorporating change-points at certain times. Estimates of KAs indicated that the absorption was slower at equivalent times and extended for CR relative to IR carvedilol. Oral clearance ofS(−)-carvedilol was 149 L/h. The IRPM and the CR doses had bioavailability (Frel) of 0.80 and 0.76, respectively, relative to the IRAM dose. The inter-subject variability in KAs was lower for the CR dosage form than the original IR dosage form. Estimation of interoccasion variability on KAs and Frel for the CR dosage form improved the fit. The model performed well in simulation and leverage analysis indicated its robustness. The model will be a useful tool for future simulation studies