Journal article
Genotype-phenotype associations of cytochrome P450 3A4 and 3A5 polymorphism with midazolam clearance in vivo
Clinical pharmacology and therapeutics, Vol.77(5), pp.373-387
05/2005
Handle:
https://hdl.handle.net/2376/112576
PMID: 15900284
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.
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Details
- Title
- Genotype-phenotype associations of cytochrome P450 3A4 and 3A5 polymorphism with midazolam clearance in vivo
- Creators
- Ping He - Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Ave, Boston, MA 02111, USAMichael H CourtDavid J GreenblattLisa L Von Moltke
- Publication Details
- Clinical pharmacology and therapeutics, Vol.77(5), pp.373-387
- Academic Unit
- Veterinary Clinical Sciences, Department of
- Publisher
- United States
- Grant note
- DK-58496 / NIDDK NIH HHS GM-61834 / NIGMS NIH HHS DA-05258 / NIDA NIH HHS AG-17880 / NIA NIH HHS RR-00054 / NCRR NIH HHS AT-01381 / NCCIH NIH HHS DA-13209 / NIDA NIH HHS MH-58435 / NIMH NIH HHS
- Identifiers
- 99900547610101842
- Language
- English
- Resource Type
- Journal article