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标题：Physiologically-based Pharmacokinetic Analysis of Grepafloxacin
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作者：Yukiko NAKAJIMA ; Kenji HATTORI ; Machiko SHINSEI 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2000
卷号：23
期号：9
页码：1077-1083
DOI：10.1248/bpb.23.1077
出版社：The Pharmaceutical Society of Japan
摘要：Grepafloxacin (GPFX) is a synthetic new quinolone antimicrobial agent that possesses an extensive tissue distribution and exhibits a strong antibacterial activity in vivo. In this study, the tissue distribution characteristics of GPFX were examined using tissue concentration-time profiles following intravenous administration to rats. Subsequently, the pharmacokinetics of GPFX were analyzed based on the physiological pharmacokinetic model. The tissue-to-plasma partition coefficients (K_p) of GPFX in rats were high in all tissues except brain. A pharmacokinetic model for rabbits, monkeys and dogs was constructed using the tissue-to-plasma free concentration ratio (K_{p, f}) of GPFX in rats to simulate the GPFX concentration-time profile in plasma following intravenous administration of GPFX to each animal. The calculation-derived concentrations correlated well with the experimentally-derived data, suggesting that there are no interspecies differences in the high tissue distribution characteristics of GPFX. The clearance rates of GPFX in humans were predicted from the pharmacokinetic parameters of rats, rabbits, monkeys and dogs by an animal scale-up method and a pharmacokinetic model for humans was constructed. The GPFX concentration-time profiles in plasma, following oral administration of GPFX to humans, were predicted within 0.5-1.0 h of mean absorption time and the calculation-derived results were in good agreement with the experimental data. Thus, it is suggested that the concentration-time profile in plasma and all human organs can be predicted from the pharmacokinetic data of animals.
关键词：grepafloxacin;physiological pharmacokinetic model;tissue distribution;animal scale-up