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- Title
Genotype-phenotype associations of cytochrome P450 3A4 and 3A5 polymorphism with midazolam clearance in vivo.
- Authors
Ping He; Court, Michael H.; Greenblatt, David J.; von Moltke, Lisa L.
- 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*VICYP3A5* 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.
- Subjects
CYTOCHROME P-450; MIDAZOLAM; BENZODIAZEPINES; GENETIC polymorphisms; GENES; DRUG metabolism; PHENOTYPES
- Publication
Clinical Pharmacology & Therapeutics, 2005, Vol 77, Issue 5, p373
- ISSN
0009-9236
- Publication type
Article