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Effects of acute renal failure on the pharmacokinetics of telithromycin in rats: negligible effects of increase in CYP3A1 on the metabolism of telithromycin

It was reported that the expression of CYP3A1 increased in rats with acute renal failure induced by uranyl nitrate (rat model of U‐ARF) compared with controls. It was shown that telithromycin was mainly metabolized via CYP3A1/2 in rats in this study. Hence, the pharmacokinetic parameters of telithromycin were compared after both intravenous and oral administration at a dose of 50 mg/kg to control rats and a rat model of U‐ARF. After intravenous administration of telithromycin to rats with U‐ARF, the AUC and renal clearance (Clr) were significantly greater (35.0% increase) and slower (99.1% decrease), respectively, than the controls. Unexpectedly, the nonrenal clearance (Clnr) of telithromycin was comparable between the two groups of rats, suggesting that CYP3A isozyme responsible for the metabolism of telithromycin seemed not to be expressed considerably in the rat model of U‐ARF. After oral administration of telithromycin to rats with U‐ARF, the AUC was also significantly greater (127% increase) than the controls and the value, 127%, was considerably greater than 35.0% after intravenous administration of telithromycin. This may be due mainly to the decrease in the intestinal first‐pass effect of telithromycin compared with controls in addition to significantly slower Clr than controls. Copyright © 2007 John Wiley & Sons, Ltd.