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
Clinical Science Department, Development Division, Kyowa Hakko Kirin Co., Ltd., Tokyo, Japan. Arzneimittel-Forschung
(Impact Factor: 0.7).
02/2012; 62(5):213-21. DOI: 10.1055/s-0032-1301883
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.
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ABSTRACT: Sexual dimorphism is not only noticed in the prevalence of many diseases, but also in multiple physiological functions in the body. This review has summarized findings from published literature on the sex differences of the pathophysiology and pharmacology of the lower urinary tract (LUT) of humans and animals. Sex differences have been found in several key areas of the LUT, such as overactive bladder, expression and function of neurotransmitter receptors in the bladder and urethra, and micturition patterns in humans and animals. It is anticipated that this review will not only evoke renewed interest for further research on the mechanism of sex differences in the pathophysiology of the LUT (especially for overactive bladder), but might also open up the possibilities for gender-based drug development by pharmaceutical industries in order to find separate cures for men and women with diseases of the LUT.
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