Effects of cysteine on the pharmacokinetics of intravenous clarithromycin in rats with protein-calorie malnutrition

Effects of cysteine on the pharmacokinetics of clarithromycin were investigated after intravenous administration of the drug at a dose of 20 mg/kg to control rats (4-week fed on 23% casein diet) and rats with PCM (protein-calorie malnutrition, 4-week fed on 5% casein diet) and PCMC (PCM treated with 250 mg/kg for oral cysteine twice daily during the fourth week). Clarithromycin has been reported to be metabolized via hepatic microsomal cytochrome P450 (CYP) 3A4 to 14-hydroxyclarithromycin (primary metabolite of clarithromycin) in human subjects. It has also been reported that in rats with PCM, CYP3A23 level decreased to 40-50% of control level, but decreased CYP3A23 level in rats with PCM completely returned to control level by oral cysteine supplementation (rats with PCMC). Human CYP3A4 and rat CYP3A23 proteins have 73% homology. In rats with PCM, the area under the plasma concentration-time curve from time zero to time infinity, AUC (567, 853 and 558 microg min/ml for control rats and rats with PCM and PCMC, respectively) and percentage of clarithromycin remaining after incubation with liver homogenate (69.6, 83.9 and 71.7%) were significantly greater than those in control rats and rats with PCMC. Moreover, in rats with PCM, the total body clearance, CL (35.3, 23.4 and 35.8 ml/min/kg), nonrenal clearance, CL(NR) (21.3, 15.2 and 24.1 ml/min/kg) and maximum velocity for the disappearance of clarithromycin after incubation with hepatic microsomal fraction, V(max) (351, 211 and 372 pmol/min/mg protein) were significantly slower than those in control rats and rats with PCMC. However, above mentioned each parameter was not significantly different between control rats and rats with PCMC. The above data suggested that metabolism of clarithromycin decreased significantly in rats with PCM as compared to control due to significantly decreased level of CYP3A23 in the rats. By cysteine supplementation (rats with PCMC), some pharmacokinetic parameters of clarithromycin (AUC, CL, CL(NR) and V(max)) were restored fully to control levels because CYP3A23 level was completely returned to control level in rats with PCMC.