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

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.