title: Genotype-phenotype associations of cytochrome P450 3A4 and 3A5 polymorphism with midazolam clearance in vivo.
abstract: The molecular basis for the wide interindividual variability of cytochrome P450 (CYP) 3A metabolic activity was studied in vivo at a genetic level. A single oral dose of midazolam was administered to 26 healthy subjects. The variability in midazolam oral clearance was 11-fold. No differences in midazolam oral clearance related to gender or ethnicity were observed. Selective sequencing of CYP3A4 and CYP3A5 genes revealed 18 single nucleotide polymorphisms (SNPs), including 8 novel CYP3A4 SNPs. Thirteen novel CYP3A4 haplotypes, 2 novel CYP3A5 haplotypes, and 1 major novel multigene haplotype ( CYP3A4*VI - CYP3A5*3A ) were also identified. No significant genotype-phenotype or haplotype-phenotype associations were found for any of the SNPs or haplotypes studied, including CYP3A4*1B , CYP3A5*3 , and CYP3A5*6 , even when ethnicity was considered. The only exceptions were the haplotype CYP3A4*VI and the multigene haplotype CYP3A4*VI - CYP3A5*3A . The carriers of the haplotype CYP3A4*VI had a 1.8-fold higher clearance of midazolam in black subjects (ANOVA on ranks, P = .028) compared with other individuals, and the carriers of the multigene haplotype CYP3A4*VI - CYP3A5*3A had a 1.7-fold higher clearance in the entire population (ANOVA on ranks, P = .012). In conclusion, these results indicate that the genetic variants identified so far in the CYP3A4 and CYP3A5 genes have only a limited impact on CYP3A-mediated drug metabolism in vivo.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Ave, Boston, MA 02111, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: He
authors.forename: Michael H
authors.initials: MH
authors.lastname: Court
authors.forename: David J
authors.initials: DJ
authors.lastname: Greenblatt
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Von Moltke
mesh_terms: D000284:Administration, Oral; D000328:Adult; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D004334:Drug Administration Schedule; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000235:genetics; D008874:Midazolam / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods / Q000706:statistics & numerical data; D010641:Phenotype; D011110:Polymorphism, Genetic
chemical_list: D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam