Nature Biotechnology 24, 531 - 536 (2006)
Published online: 5 May 2006; | doi:10.1038/nbt1195
In silico pharmacogenetics of warfarin metabolismYingying Guo1, Paul Weller2, Erin Farrell1, Paul Cheung2, Bill Fitch2, Douglas Clark2, Shao-yong Wu3, Jianmei Wang1, Guochun Liao1, Zhaomei Zhang1, John Allard1, Janet Cheng1, Anh Nguyen1, Sharon Jiang1, Steve Shafer4, Jonathan Usuka1, Mohammad Masjedizadeh3
& Gary Peltz11
Departments of Genetics and Genomics, Palo Alto S3-1, 3431 Hillview Ave., Palo Alto, California 94304, USA. 2
Drug Metabolism and Pharmacokinetics, Palo Alto S3-1, 3431 Hillview Ave., Palo Alto, California 94304, USA. 3
Chemical Services, Roche Palo Alto S3-1, 3431 Hillview Ave., Palo Alto, California 94304, USA. 4
Stanford University Department of Anesthesiology, Palo Alto, California 94305, USA.
Correspondence should be addressed to Gary Peltz gary.peltz@roche.com Pharmacogenetic approaches can be instrumental for predicting individual differences in response to a therapeutic intervention. Here we used a recently developed murine haplotype-based computational method to identify a genetic factor regulating the metabolism of warfarin, a commonly prescribed anticoagulant with a narrow therapeutic index and a large variation in individual dosing. After quantification of warfarin and nine of its metabolites in plasma from 13 inbred mouse strains, we correlated strain-specific differences in 7-hydroxywarfarin accumulation with genetic variation within a chromosomal region encoding cytochrome P450 2C (Cyp2c) enzymes. This computational prediction was experimentally confirmed by showing that the rate-limiting step in biotransformation of warfarin to its 7-hydroxylated metabolite was inhibited by tolbutamide, a Cyp2c isoform-specific substrate, and that this transformation was mediated by expressed recombinant Cyp2c29. We show that genetic variants responsible for interindividual pharmacokinetic differences in drug metabolism can be identified by computational genetic analysis in mice.
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