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Association of Genotypes of the CYP3A Cluster with Midazolam Disposition in Vivo

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Association of Genotypes of the CYP3A Cluster with Midazolam Disposition in Vivo The Pharmacogenomics Journal (2009) 9, 319–326 & 2009 Nature Publishing Group All rights reserved 1470-269X/09 $32.00 www.nature.com/tpj ORIGINAL ARTICLE Association of genotypes of the CYP3A cluster with midazolam disposition in vivo J Miao1,3, Y Jin1, RL Marunde1, The genes that encode for CYP3A4 and CYP3A5 are located in the same 2 2 region (CYP3A cluster) on chromosome 7. Midazolam (MDZ) is a substrate S Kim , S Quinney , for both CYP3A4 and CYP3A5. We hypothesize that MDZ disposition in vivo is 1 2 1 M Radovich ,LLi and SD Hall associated with genotypes of the CYP3A cluster. A meta-analysis of the pharmacokinetic (PK) parameters from seven clinical trials was carried out, in 1Division of Clinical Pharmacology, Department of Medicine, Indiana University School of which MDZ was administered both intravenously and orally. DNA samples Medicine, Indianapolis, IN, USA; 2Division of were available from 116 patients. There were significant ethnic differences in Biostatistics, Department of Medicine, Indiana the allelic frequencies of these four common single-nucleotide polymorph- University School of Medicine, Indianapolis, IN, isms (SNPs) in the CYP3A cluster. Significant linkage disequilibrium was USA and 3Division of Clinical Pharmacology, West China Hospital, Sichuan University, found between CYP3A5*3 and CYP3A4*1A in Caucasians, and between Chengdu, Sichuan, PR China CYP3A5*1 and CYP3A4*1B in African Americans. There were no differences in MDZ disposition in vivo between different genotypes, haplotypes and Correspondence: diplotypes in the CYP3A cluster (P40.05). No significant differences in Dr L Li, Department of Medicine/Biostatistics, MDZ PK parameters were observed between Caucasians and African Indiana University, HITS 3000, 410 West 10th Street, Indianapolis, IN 46202, USA. Americans. Women had higher weight-corrected systemic and oral clearance E-mail: [email protected] than men, but dose-adjusted AUC and bioavailability differences were not observed between sexes. The clinical importance of elevated CYP3A activity in women remains to be determined. The rGC’s of MDZ PK parameters were between 0.3 and 13.6%. In conclusion, the meta-analysis of seven studies suggests that environmental factors explain the majority of CYP3A activity variation. Further studies are necessary to define the functional significance of SNPs in the CYP3A cluster and the effects of CYP3A genotypes on MDZ disposition in vivo. The Pharmacogenomics Journal (2009) 9, 319–326; doi:10.1038/tpj.2009.21; published online 9 June 2009 Keywords: CYP3A; genetic/environmental variations; midazolam Introduction The human CYP3A enzyme subfamily is involved in the oxidative metabolism of a wide range of substrates, including more than 50% of all currently marketed drugs, endogenous steroids and xenobiotic chemicals.1,2 CYP3A-mediated activity shows approximately 10-fold difference between individuals, which presents a challenge in predicting drug effect and safety.3 Although concomitant drugs and environment factors partly account for the variability, genetic polymorphisms and variation in expression may play a critical role in between- subject variability of CYP3A activity.4,5 The CYP3A gene cluster, which is located on chromosome 7q22 and spans B220 kb, consists of four genes, including CYP3A4, CYP3A5, CYP3A7 and 6 Received 24 November 2008; accepted 16 CYP3A43. CYP3A4 and CYP3A5 are the major metabolism enzymes in adults, March 2009; published online 9 June 2009 and are expressed primarily in the liver and small intestine. CYP3A7 is expressed CYP3A genetic/non-genetic in vivo variations with MDZ J Miao et al 320 in fetal liver and plays an important role in the metabolism tion of MDZ reflects only hepatic CYP3A activity, whereas of endogenous substrates. CYP3A43 is expressed at very orally administered MDZ is a measure of intestinal and low levels in adult human livers. Its contribution to hepatic CYP3A activities.25–27 Simultaneous i.v. and oral the elimination of CYP3A substrates is regarded to be (p.o.) MDZ administration has been used to examine the negligible.7,8 individual contributions of intestinal and hepatic CYP3A to Although a number of single-nucleotide polymorphisms metabolism.25–27 (SNPs) at the CYP3A4 locus have been identified, few of Although remarkable ethnic differences exist within the them occur frequently enough to contribute to variations in CYP3A cluster structure, the genetic component of varia- CYP3A activity. As no evidence has shown functionally bility (that is, between-subject variability) remains uncer- important allelic mutations in the CYP3A4 coding region, tain.28–30 Some studies also suggest that there are sex the between-subject variability in CYP3A4 activity may be differences in CYP3A activity, but the results are incon- the result of transcriptional regulation.1,9–11 For instance, sistent.31–33 The objectives of our study are to investigate the CYP3A4*1B (À392A4G) is a common SNP located in the whether i.v. and p.o. MDZ disposition in vivo is associated 50 promoter region. The role of this polymorphism on with genotypes of the CYP3A cluster, ethnicity, sex or age in enzyme activity in vivo remains controversial.9 Functional healthy volunteers and to understand the genetic compo- SNPs are more commonly observed in the CYP3A5 gene. The nent of its variability. CYP3A5*3 (6989A4G) SNP in intron 3 introduces a cryptic splice site that results in a frame shift and truncated Materials and methods protein.12 The CYP3A5*6 (14690G4A) SNP in exon 7 leads to a splicing defect, and the CYP3A5*7 (insertion at Study design 27131_32) SNP in exon 11 results in a premature stop We reviewed seven clinical trials conducted from 1998 to codon.13,14 It has been suggested that CYP3A5*6 and 2003 by our research team (Table 1). In each study, single- CYP3A5*7 be considered together in conjunction with dose MDZ was administrated both i.v. and p.o. In five CYP3A5*3 in order to predict significantly diminished studies, subjects were simultaneously administered a single CYP3A5 expression.4 Earlier studies have shown that in i.v. dose (0.05 mg kgÀ1 over 30 min) of MDZ and an oral dose Caucasians CYP3A4*1B is in strong linkage disequilibrium of 15N-MDZ (3 mg) after an overnight fast. In two additional with the functional CYP3A5*1. About 80% of Caucasians are studies, oral MDZ (4 mg) was administered 24 h after the i.v. homozygous for the CYP3A5*3 and CYP3A4*1A alleles.15,16 dose. All drugs and food known to affect CYP3A activity Midazolam (MDZ), which can be administrated both were prohibited before and during the studies. For each intravenously and orally, is selectively metabolized by subject, blood samples for MDZ concentrations were CYP3A4 and CYP3A5 to its primary metabolite, 10-hydro- obtained over a period of 12–24 h. The sample sizes varied xymidazolam, and is not a substrate of P-glycoprotein.17,18 among studies (Table 1). The MDZ serum concentrations MDZ shows most of the desired characteristics to be used as were determined using a previously published method.34,35 a probe to measure CYP3A activity, although MDZ clearance PK parameter estimates were calculated using non-compart- may be influenced by hepatic blood flow.19–24 Systemic and mental methods (WinNonLin 4.0; Pharsight, Mountain apparent oral clearances of MDZ are pharmacokinetic (PK) View, CA, USA). Dose-adjusted i.v. and p.o. area under the parameters recognized as biomarkers for hepatic and concentration–time curve (AUC), weight-corrected i.v. and intestinal CYP3A activity.23,25 Intravenous (i.v.) administra- p.o. clearance (CL), and bioavailability (F) were used as MDZ Table 1 Characteristics of the seven MDZ clinical trials Study title Time Number Number of Published information of patients DNA samples Assessment of the contribution of intestinal CYP3A to the first pass 2002 16 13 Quinney et al.48 metabolism of midazolam in elderly volunteers (643) The effect of age, sex, and rifampin administration on intestinal 2002 52 24 Gorski et al.49 and hepatic cytochrome P450 3A activity (676) The effect of hormone replacement therapy on CYP3A activity (684) 1998 36 17 Gorski et al.34 The effect of age and gender on the duration of CYP3A inhibition 2001 15 11 Not published by clarithromycin in humans (855) The effect of clarithromycin administration on intestinal and hepatic 2002 13 8 Not published CYP3A activity in healthy volunteers: a pilot study (887A) Effect of multiple doses of ketoconazole on cytochrome P450 3A 2003 24 24 Not published activity (1148c) Relationship between CYP3A5 genotypes and effect of verapamil 2002 26 20 Jin et al.14 on midazolam pharmacokinetics (1056) The Pharmacogenomics Journal CYP3A genetic/non-genetic in vivo variations with MDZ J Miao et al 321 PK parameters, as dosages were different in these seven trials Results and body size seems to be an important determinant of between-subject variability.36 Blood was also collected for Study characteristics DNA analysis. Pharmacokinetic parameters of MDZ were collected from seven clinical trials, in which single-dose MDZ was admini- Study population strated both i.v. and p.o. Results of some these seven studies These seven clinical trials were approved by the Institutional have been published earlier (Table 1). Review Board of Indiana University–Purdue University Indianapolis and informed consent was obtained from each Subject characteristics of the 176 volunteers who participated. Subjects were A total of 116 subjects in these seven trials had both MDZ healthy as determined by medical history, physical exam- disposition data and CYP3A cluster genotype data and were ination, 12-lead electrocardiogram and laboratory screen- therefore used in this analysis. Among these 116 subjects, 64 ing. DNA samples were collected from 116 subjects among subjects participated in only one trial and 22 subjects the cohort (Table 1). participated in 2–3 different clinical trials. The character- istics of all the 116 subjects and in groups based on the Genotyping methods CYP3A5 haplotype are summarized in Table 2.
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