title: Novel LC-MS/MS method for simultaneous quantification of KW-7158, a new drug candidate for urinary incontinence and bladder hyperactivity, and its metabolites in rat plasma: a pharmacokinetic study in male and female rats.
abstract: To investigate the pharmacokinetics of KW-7158 (CAS 214763-95-8), a new drug candidate for urinary incontinence and bladder hyperactivity, in male and female rats, we developed and validated a simultaneous quantification method for KW-7158 and its 2 metabolites, M1 and M2, in plasma using high performance liquid chromatography-tandem mass spectrometry with positive/negative ion-switching scan mode. The method was selective and sensitive to KW-7158, M1 and M2 with overall precision expressed as coefficient of variance less than 11.8% and accuracy (relative error) within ± 13.7% in intra- and inter-assay variability. This method was used to determine the plasma concentration of KW-7158, M1 and M2 after intravenous and oral administration of KW-7158 in male and female rats. KW-7158 was detected as a primary constituent in plasma in both administration routes. M1 was a major metabolite with the concentration ratio of 10-20% of KW-7158, and M2 was a minor metabolite. Pharmacokinetics of KW-7158 after oral administration was considered to be linear at doses from 0.01 to 1 mg/kg. Bioavailability was relatively high with the values of 69.4 ± 17.1% and 82.6 ± 20.0% at a dose of 0.1 mg/kg in male and female rats, respectively. There was a little gender difference in pharmacokinetics of KW-7158 and its metabolites in rats.
authors.affiliation: Clinical Science Department, Development Division, Kyowa Hakko Kirin Co., Ltd., Tokyo, Japan. hiroshi.maeda@kyowa-kirin.co.jp
authors.forename: H
authors.initials: H
authors.lastname: Maeda
authors.forename: K
authors.initials: K
authors.lastname: Fujita
authors.forename: H
authors.initials: H
authors.lastname: Kobayashi
authors.forename: J
authors.initials: J
authors.lastname: Ushiki
authors.forename: T
authors.initials: T
authors.lastname: Nakanishi
authors.forename: I
authors.initials: I
authors.lastname: Tamai
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001582:Benzothiepins / Q000032:analysis* / Q000493:pharmacokinetics; D001711:Biotransformation; D002138:Calibration; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D005260:Female; D007275:Injections, Intravenous; D057230:Limit of Detection; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D015203:Reproducibility of Results; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry; D001750:Urinary Bladder, Neurogenic / Q000188:drug therapy*; D014549:Urinary Incontinence / Q000188:drug therapy*
chemical_list: D001582:Benzothiepins; C466985:KW 7158