Association of genotypes of the CYP3A cluster with midazolam disposition in vivo

Abstract

The genes that encode for CYP3A4 and CYP3A5 are located in the same region (CYP3A cluster) on chromosome 7. Midazolam (MDZ) is a substrate for both CYP3A4 and CYP3A5. We hypothesize that MDZ disposition in vivo is associated with genotypes of the CYP3A cluster. A meta-analysis of the pharmacokinetic (PK) parameters from seven clinical trials was carried out, in which MDZ was administered both intravenously and orally. DNA samples were available from 116 patients. There were significant ethnic differences in the allelic frequencies of these four common single-nucleotide polymorphisms (SNPs) in the CYP3A cluster. Significant linkage disequilibrium was found between CYP3A5*3 and CYP3A4*1A in Caucasians, and between CYP3A5*1 and CYP3A4*1B in African Americans. There were no differences in MDZ disposition in vivo between different genotypes, haplotypes and diplotypes in the CYP3A cluster (P40.05). No significant differences in MDZ PK parameters were observed between Caucasians and African Americans. Women had higher weight-corrected systemic and oral clearance 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 r GC '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.

Sex-Dependent Differences in Cytochrome P450 3A Activity as Assessed by Midazolam Disposition in Humans: A Meta-Analysis

“…Miao et al (2009) concluded that women exhibited 19% higher weight-corrected systemic clearance and 38% higher oral clearance than men (P Ͻ 0.05). This study reviewed the data from seven clinical studies, which were previously conducted by their research team, but only included subjects whose DNA samples were available.…”

“…The oral clearance data of this study were surprisingly higher than those of other included studies. As a result, the retrospective study by Miao et al (2009) is at a higher risk of bias compared with that for a prospective study. In the other retrospective study, Chen et al (2006b) found that women exhibited 11% higher mean weight-corrected MDZ systemic clearance and 28% higher oral clearance than men (P Յ 0.01).…”

“…For example, mean MDZ clearances were greater in women in several investigations, reaching statistical significance in some (Greenblatt et al, 1984;Gorski et al, 1998Gorski et al, , 1999Zhu et al, 2003;Chen et al, 2006c;Chung et al, 2006;Kharasch et al, 2007;Hu et al, 2009), whereas other studies found equivalence (Kashuba et al, 1998;Dresser et al, 2003;Floyd et al, 2003;Gorski et al, 2003;Eap et al, 2004;Chen et al, 2006a) or even insignificantly higher clearances in men (Thummel et al, 1996). Results of the largest-scale investigation (41 women and 58 men) showed that systemic clearances were 30% greater in women, but there was no sex difference for oral MDZ (Kharasch et al, 2007).There were two retrospective studies on this topic, and both studies showed significant sex-dependent differences (Chen et al, 2006b;Miao et al, 2009). Miao et al (2009) concluded that women exhibited 19% higher weight-corrected systemic clearance and 38% higher oral clearance than men (P Ͻ 0.05).…”

“…There were two retrospective studies on this topic, and both studies showed significant sex-dependent differences (Chen et al, 2006b;Miao et al, 2009). Miao et al (2009) concluded that women exhibited 19% higher weight-corrected systemic clearance and 38% higher oral clearance than men (P Ͻ 0.05).…”

Analysis of the CYP3A4*1B Gene Variant in an Iranian Population: Pilot Base Study

“…Pharmacogenetic studies show that genetic variations in this gene and other genes of CYP450 superfamily (specially polymorphism) can affect metabolism process of drugs [1]. Peer review studies about CYP3A4*1B have shown different frequency of variant allele in population with different ethnic background [17], [18], [19], [15], [14], [20], [15`]. We showed 3% allele frequency for variant allele in studied population as one of local country in Asian population.…”