title: In silico pharmacogenetics of warfarin metabolism.
abstract: 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.
authors: Department of Genetics and Genomics, Roche Palo Alto S3-1, 3431 Hillview Ave., Palo Alto, California 94304, USA.
authors: Yingying
authors: Y
authors: Guo
authors: Paul
authors: P
authors: Weller
authors: Erin
authors: E
authors: Farrell
authors: Paul
authors: P
authors: Cheung
authors: Bill
authors: B
authors: Fitch
authors: Douglas
authors: D
authors: Clark
authors: Shao-yong
authors: SY
authors: Wu
authors: Jianmei
authors: J
authors: Wang
authors: Guochun
authors: G
authors: Liao
authors: Zhaomei
authors: Z
authors: Zhang
authors: John
authors: J
authors: Allard
authors: Janet
authors: J
authors: Cheng
authors: Anh
authors: A
authors: Nguyen
authors: Sharon
authors: S
authors: Jiang
authors: Steve
authors: S
authors: Shafer
authors: Jonathan
authors: J
authors: Usuka
authors: Mohammad
authors: M
authors: Masjedizadeh
authors: Gary
authors: G
authors: Peltz