title: Species differences in metabolism of ripasudil (K-115) are attributed to aldehyde oxidase.
abstract: 1. We examined the metabolism of ripasudil (K-115), a selective and potent Rho-associated coiled coil-containing protein kinase (ROCK) inhibitor, by in vitro and in vivo studies. 2. First, we identified metabolites and metabolic enzymes involved in ripasudil metabolism. Species differences were observed in metabolic clearance and profiles of metabolites in liver S9 fraction and hepatocytes. In addition, ripasudil was metabolised in humans and monkey S9 without nicotinamide adenine dinucleotide phosphate (NADPH). Studies using specific inhibitors and human recombinant enzyme systems showed that M1 (main metabolite in humans) formation is mediated by aldehyde oxidase (AO). 3. Therefore, we developed ripasudil as an ophthalmic agent. First, we compared the pharmacokinetic profiles of ripasudil in humans and rats. The results indicated rapid disappearance of ripasudil from the circulation after instillation in humans and its level remained relatively high only in M1. In contrast, we found six metabolites from M1 to M6 in plasma after oral administration to rats. 4. Analysis of enzyme kinetics using S9 showed that the formation of M1 is the major metabolic pathway of ripasudil in humans even though CYP3A4/3A5 and CYP2C8/3A4/3A5 were associated with the formation of M2 and M4, respectively. In conclusion, AO causes differences in ripasudil metabolism between species.
authors.affiliation: a Tokyo New Drug Research Laboratories, Kowa Co., Ltd. , Tokyo , Japan and.|b Department of Pharmaceutics , Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama , Toyama , Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Isobe
authors.affiliation: a Tokyo New Drug Research Laboratories, Kowa Co., Ltd. , Tokyo , Japan and.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ohta
authors.affiliation: a Tokyo New Drug Research Laboratories, Kowa Co., Ltd. , Tokyo , Japan and.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Kaneko
authors.affiliation: a Tokyo New Drug Research Laboratories, Kowa Co., Ltd. , Tokyo , Japan and.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kawai
keywords: Glaucoma; ROCK; S9; hepatocyte; instillation; non-cytochrome P-450; pharmacokinetics