title: Oxidation of R- and S-omeprazole stereoselectively mediated by liver microsomal cytochrome P450 2C19 enzymes from cynomolgus monkeys and common marmosets.
abstract: Racemic omeprazole has been used for clinically treating gastric acid-related diseases and also as a typical human cytochrome P450 (P450) 2C19 probe substrate in preclinical studies. S-Omeprazole has been developed as a single enantiomer medicine, which has been reported not to be associated with polymorphic human P450 2C19 phenotypes. In this study, 5-hydroxylation and sulfoxidation activities, with respect to stereoselective R- and S-omeprazole oxidations by liver microsomes from experimental animals including non-human primates and humans, were investigated in vitro. Liver microsomes from humans, cynomolgus monkeys, and mice preferentially mediated R-omeprazole 5-hydroxylations, however those from marmosets, minipigs, dogs, and rats preferentially mediated S-omeprazole 5-hydroxylations. High catalytic activities were observed for recombinant human P450 2C19 in R-omeprazole 5-hydroxlations, cynomolgus monkey P450 2C19 in both R- and S-omeprazole 5-hydroxlations, and marmoset P450 2C19 in S-omeprazole 5-hydroxlations. On the other hand, human, cynomolgus monkey, and marmoset P450 3A enzymes preferentially mediated S-omeprazole sulfoxidations. Correlation and kinetic analyses revealed a high affinity of polymorphic cynomolgus monkey and marmoset liver microsomal P450 2C19 enzymes with respect to R- and S-omeprazole 5-hydroxylations, respectively, and a high capacity of cynomolgus monkey and marmoset liver microsomal P450 3A4 for omeprazole 5-hydroxylations and sulfoxidations. R-and S-omeprazole 5-hydroxylation activities in cynomolgus monkey and marmoset liver microsomes were significantly different among wild-type, heterozygous, and homozygous animals genotyped for cynomolgus monkey P450 2C19 p.[(Phe100Asn; Ala103Val; Ile112Leu)] and for marmoset P450 2C19 p.[(Phe7Leu; Ser254Leu; Ile469Thr)], respectively. The results of this study demonstrate polymorphic cynomolgus monkey and marmoset P450 2C19-dependent omeprazole oxidation activities with individual variations similar to humans.
authors.affiliation: Showa Pharmaceutical University, Machida, Tokyo, Japan.
authors.forename: Shotaro
authors.initials: S
authors.lastname: Uehara
authors.affiliation: Showa Pharmaceutical University, Machida, Tokyo, Japan.
authors.forename: Mirai
authors.initials: M
authors.lastname: Kawano
authors.affiliation: Showa Pharmaceutical University, Machida, Tokyo, Japan.
authors.forename: Norie
authors.initials: N
authors.lastname: Murayama
authors.affiliation: Shin Nippon Biomedical Laboratories, Ltd., Kainan, Wakayama, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Uno
authors.affiliation: Shin Nippon Biomedical Laboratories, Ltd., Kainan, Wakayama, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Utoh
authors.affiliation: Central Institute for Experimental Animals, Kawasaki, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Central Institute for Experimental Animals, Kawasaki, Japan; Keio Advanced Research Center, Keio University, Minato-ku, Tokyo, Japan.
authors.forename: Erika
authors.initials: E
authors.lastname: Sasaki
authors.affiliation: Showa Pharmaceutical University, Machida, Tokyo, Japan. Electronic address: hyamazak@ac.shoyaku.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
mesh_terms: D000818:Animals; D000897:Anti-Ulcer Agents / Q000737:chemistry / Q000378:metabolism*; D055162:Biocatalysis; D001711:Biotransformation; D002144:Callithrix; D065731:Cytochrome P-450 CYP2C19 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004285:Dogs; D006801:Humans; D006900:Hydroxylation; D008252:Macaca fascicularis; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology* / Q000378:metabolism; D062105:Molecular Docking Simulation; D009853:Omeprazole / Q000737:chemistry / Q000378:metabolism*; D010084:Oxidation-Reduction; D011110:Polymorphism, Genetic; D054328:Proton Pump Inhibitors / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013045:Species Specificity; D013237:Stereoisomerism; D013552:Swine; D013556:Swine, Miniature
chemical_list: D000897:Anti-Ulcer Agents; D054328:Proton Pump Inhibitors; D011994:Recombinant Proteins; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D009853:Omeprazole
keywords: CYP2C19; Genotyping; Macaque; Marmoset; Stereoselectivity