Assessing Aging-Effect on CYP3A Activity in Rats with Probe Substrate Mosapride

• Main Authors: Yin-YinTung, 董茵茵
• Other Authors: Chen-Hsi Chou
• Format: Others
• Language: zh-TW
• Published: 2016
• Online Access: http://ndltd.ncl.edu.tw/handle/ad33z7

碩士 === 國立成功大學 === 臨床藥學與藥物科技研究所 === 104 === Age of subjects can play a key role in variability in pharmacokinetics and thus efficacy and safety of drugs. CYP3A is one of the most important CYP450 subfamilies with great variation. The use of CYP3A phenotyping probes in drug therapy is of great importance. In this study, the age-related changes in the pharmacokinetics of a putative CYP3A phenotyping probe mosapride and a CYP3A substrate rilpivirine in rats were investigated. The disposition kinetics of mosapride and rilpivirine in rats displayed two-compartmental characteristics. Aging significantly affected the clearance of both drugs in male rats, but not in female rats. The clearance of CYP3A substrates mosapride and rilpivirine in rats was gender-dependent. The systemic exposure of both drugs in female rats was consistently greater than that in male rats. The clearance of mosapride and rilpivirine was maximal at 9-week-old in male rats and decreased after puberty. In female rats, the clearance of the drugs did not change significantly over the entire age range studied. The relationship between mosapride clearance and hepatic CYP3A2 content can be described by well-stirred clearance model. The correlation between mosapride clearance and rilpivirine clearance was relatively good with a correlation coefficient of 0.77. The systemic exposure of CYP3A probe mosapride in rats, in terms of AUC, can be precisely predicted using a single point plasma concentration. The clearance of CYP3A substrates mosapride and rilpivirine in rats was gender-dependent. Aging significantly affected the clearance of both drugs in male rats, but not in female rats. The correlation between mosapride clearance and rilpivirine clearance was relatively good, supporting the applicability of mosapride as an in vivo CYP3A probe in rats.