Joo H Lee1, Myung G Lee. 1. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul, 151-742, South Korea.
Abstract
PURPOSE: It has been reported that telithromycin is primarily metabolized via hepatic CYP3A1/2 in rats, the expression and/or mRNA level of hepatic CYP3A1/2 increase in rat model of diabetes mellitus induced by alloxan (DMIA) or streptozotocin (DMIS), and intestinal CYP3A1/2 enzyme activity decreases in rat model of DMIS. Thus, the pharmacokinetic changes of telithromycin in both models of diabetes mellitus compared with those in the control rats were evaluated. METHODS: Telithromycin was administered (50 mg/kg) intravenously or orally to both rat models of diabetes and their respective control rats. RESULTS: After intravenous administration of telithromycin to both models of diabetes, the non-renal clearance (CLNR) was significantly faster (32.3 and 53.1% increase for rat models of DMIA and DMIS, respectively) and the AUC was significantly smaller (25.0 and 33.8% decrease, respectively) than those in their respective controls. However, after oral administration of telithromycin, the AUC was comparable to that in their respective controls. CONCLUSIONS: The faster CLNR after intravenous administration was due to increased hepatic CYP3A1/2 in both models of diabetes. The comparable AUC after oral administration was mainly due to decreased intestinal CYP3A1/2 activity. Alloxan and streptozotocin appear to influence some pharmacokinetics of telithromycin in a different fashion.
PURPOSE: It has been reported that telithromycin is primarily metabolized via hepatic CYP3A1/2 in rats, the expression and/or mRNA level of hepatic CYP3A1/2 increase in rat model of diabetes mellitus induced by alloxan (DMIA) or streptozotocin (DMIS), and intestinal CYP3A1/2 enzyme activity decreases in rat model of DMIS. Thus, the pharmacokinetic changes of telithromycin in both models of diabetes mellitus compared with those in the control rats were evaluated. METHODS:Telithromycin was administered (50 mg/kg) intravenously or orally to both rat models of diabetes and their respective control rats. RESULTS: After intravenous administration of telithromycin to both models of diabetes, the non-renal clearance (CLNR) was significantly faster (32.3 and 53.1% increase for rat models of DMIA and DMIS, respectively) and the AUC was significantly smaller (25.0 and 33.8% decrease, respectively) than those in their respective controls. However, after oral administration of telithromycin, the AUC was comparable to that in their respective controls. CONCLUSIONS: The faster CLNR after intravenous administration was due to increased hepatic CYP3A1/2 in both models of diabetes. The comparable AUC after oral administration was mainly due to decreased intestinal CYP3A1/2 activity. Alloxan and streptozotocin appear to influence some pharmacokinetics of telithromycin in a different fashion.