title: Slow R-warfarin 7-hydroxylation mediated by P450 2C19 genetic variants in cynomolgus monkeys in vivo.
abstract: Cynomolgus monkeys are widely used as non-human primate species in preclinical studies, due to their close evolutionary relationship to humans. Monkey cytochrome P450 2C19 (formerly known as P450 2C75), highly homologous to human P450 2C19, has been identified to be R-warfarin 7-hydroxylase in cynomolgus monkeys. In the present study, the in vivo pharmacokinetics of stereoselective warfarin and metabolites at a dose of 1.0mg/kg were investigated after oral and intravenous administration of racemic warfarin to fasted male cynomolgus monkeys (n=11, from Indochina, 4-8 years of age, 3.5-7.4kg of body weight), which had been genotyped for P450 2C19 [c.298TT>AA; c.308C>T; and c.334ATC>CTT]. Kinetic parameters for S-warfarin were not different among the homozygous mutant, heterozygous mutant, and wild type groups; however, values of elimination half-lives, area under the curves, and total body clearance of R-warfarin in the homozygous mutant group showed one-order differences from those values in the wild type group after oral or intravenous administration. R-Warfarin 7-hydroxylations in vivo in homozygous mutant groups were slow compared to wild type or heterozygous mutant groups. These results demonstrate that inter-animal variations of R-warfarin clearance in cynomolgus monkeys are associated with P450 2C19 genetic variants [p.Phe100Asn, p.Ala103Val, and p.Ile112Leu]. Because some interindividual variability of P450 2C-dependent drug metabolism in cynomolgus monkeys, similarly in humans, is accounted for by polymorphic P450 2C19 variants, genotyping of drug metabolism enzymes should be considered before and after P450-dependent drug metabolism testing and evaluations in cynomolgus monkeys.
authors: Shin Nippon Biomedical Laboratories, Ltd., Kainan, Wakayama 642-0017, Japan; Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan. Electronic address: uto-masahiro@snbl.co.jp.
authors: Masahiro
authors: M
authors: Utoh
authors: Shin Nippon Biomedical Laboratories, Ltd., Kainan, Wakayama 642-0017, Japan.
authors: Takahiro
authors: T
authors: Yoshikawa
authors: Shin Nippon Biomedical Laboratories, Ltd., Kainan, Wakayama 642-0017, Japan.
authors: Yoshiharu
authors: Y
authors: Hayashi
authors: Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
authors: Makiko
authors: M
authors: Shimizu
authors: Shin Nippon Biomedical Laboratories, Ltd., Kainan, Wakayama 642-0017, Japan.
authors: Kazuhide
authors: K
authors: Iwasaki
authors: Shin Nippon Biomedical Laboratories, Ltd., Kainan, Wakayama 642-0017, Japan.
authors: Yasuhiro
authors: Y
authors: Uno
authors: Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan. Electronic address: hyamazak@ac.shoyaku.ac.jp.
authors: Hiroshi
authors: H
authors: Yamazaki
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000737:chemistry / Q000493:pharmacokinetics*; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics / Q000378:metabolism*; D006900:Hydroxylation; D008252:Macaca fascicularis; D013237:Stereoisomerism; D014859:Warfarin / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D065731:Cytochrome P-450 CYP2C19
keywords: CYP2C19; Cynomolgus monkey; Genotyping; S-warfarin; Stereoselectivity