Pharmacokinetics of clarithromycin in rats with acute renal failure induced by uranyl nitrate

Abstract

In rats pretreated with dexamethasone (an inducer of CYP3A1/2 in rats) and troleandomycin (an inhibitor of CYP3A1/2 in rats), the area under the plasma concentration–time curve from time zero to time infinity (AUC) values of clarithromycin were significantly smaller (365 compared with 600µgmin/ml) and greater (1410 compared with 581µg min/ml), respectively, than those in control rats. This indicated that clarithromycin was metabolized via CYP3A1/2 in rats. The expression of CYP3A1(23) increased in rats with acute renal failure induced by uranyl nitrate (rats with U‐ARF). Hence, it could be expected that AUC of clarithromycin could be smaller in rats with U‐ARF. However, after intravenous administration of clarithromycin at a dose of 20mg/kg, the AUC and time‐averaged total body (Cl) and nonrenal (Cl_nr) clearance values were comparable between the two groups of rats. The 9000 × g supernatant fraction of liver homogenates in rats with U‐ARF had comparable metabolic activities for clarithromycin compared with those in control rats, suggesting that the CYP3A isozyme responsible for metabolism of clarithromycin seemed not to be expressed considerably in the rats. This could explain the comparable AUC, Cl and Cl_nr values of clarithromycin between the two groups of rats. Copyright © 2004 John Wiley & Sons, Ltd.