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: H Maeda, K Fujita, H Kobayashi, J Ushiki, T Nakanishi, I Tamai
• Journal: Arzneimittel-Forschung (Arzneimittelforschung) Vol. 62 Issue 5 Pg. 213-21 (May 2012) ISSN: 0004-4172 [Print] Germany
• PMID: 22344572 (Publication Type: Journal Article)
• Copyright: © Georg Thieme Verlag KG Stuttgart · New York.

Chemical References

• Benzothiepins
• KW 7158

Topics

• Administration, Oral
• Animals
• Benzothiepins (analysis, pharmacokinetics)
• Biotransformation
• Calibration
• Chromatography, High Pressure Liquid
• Chromatography, Liquid
• Female
• Injections, Intravenous
• Limit of Detection
• Male
• Mass Spectrometry
• Microsomes, Liver (metabolism)
• Rats
• Reproducibility of Results
• Spectrometry, Mass, Electrospray Ionization
• Tandem Mass Spectrometry
• Urinary Bladder, Neurogenic (drug therapy)
• Urinary Incontinence (drug therapy)