p450 - publications
First report of warfarin dose requirements in patients possessing the CYP2C9*12 allele.
Clin Chim Acta. 2013 May 17;
Authors: O'Brien TJ, Kidd RS, Richard CA, Ha NH, Witcher P, Tran LV, Barbour A, Tuck M, McIntosh SD, Douglas JN, Harralson AF
BACKGROUND: Warfarin is the most frequently prescribed anticoagulant in North America and Europe. It is administered as a racemate, but S-warfarin is principally responsible for its anticoagulant activity. Cytochrome P450 (CYP) 2C9 is the enzyme primarily responsible for the metabolism of S-warfarin. Numerous variant alleles of CYP2C9 have been identified. The CYP2C9*12 (rs9332239) allele harbors a P489S substitution in CYP2C9 which has been shown to result in a 40% decline in catalytic activity in vitro. CASES: Four Caucasian patients with a low mean weekly warfarin dose were genotyped for CYP2C9, VKORC1 and APOE variant alleles. None of the four patients carried the common CYP2C9 variant alleles (*2, *3, *5, *6, *7, *8, *9, *11, *13) despite a relatively low mean weekly warfarin dose (MWWD = 23.4 ± 7.94 mg) compared to 208 patients carrying the CYP29C9*1 genotype (32.2 ± 12.65 mg). Given that CYP2C9*12 confers decreased in vitro activity to the enzyme, we investigated whether these patients carried this allele. All 4 patients were CYP2C9*12 CT heterozygotes. Individual comparisons with patients possessing the same VKORC1 and APOE genotypes also demonstrated lower dose requirements in the patients that possessed CYP2C9*12 allele. CONCLUSIONS: There are no reports of the clinical impact of rs9332239 on CYP2C9 substrates. This is the first report of patients with the rare CYP2C9*12 genotype and lower warfarin dose requirements.
PMID: 23688605 [PubMed - as supplied by publisher]