Effects of cysteine on metformin pharmacokinetics in rats with protein-calorie malnutrition: partial restoration of some parameters to control levels

Abstract

Metformin is metabolized primarily via hepatic microsomal cytochrome P450 (CYP)2C11, CYP2D1 and CYP3A1/2 in rats. The expression and mRNA levels of hepatic CYP2C11 and CYP3A1/2 are decreased in rats with protein-calorie malnutrition (PCM), but these levels are fully or partially restored to control levels in PMC rats by oral cysteine supplementation (PCMC rats). Thus, it would be expected that the pharmacokinetic parameters of metformin in PCM rats would be returned to control levels in PCMC rats. Metformin was administered i.v. (100 mg kg−1) and orally (100 mg kg−1) to control, CC (control rats with oral cysteine supplementation), PCM and PCMC rats. The following pharmacokinetic parameters of metformin following i.v. administration were restored from levels in PCM rats to levels in control rats in PCMC rats: intrinsic clearance (0.0350, 0.0309, 0.0253 and 0.0316 mL min−1 mg−1 protein for control, CC, PCM, and PCMC rats, respectively), total area under the plasma concentration-time curve from time zero to time infinity (AUC; 4110, 4290, 5540 and 4430 μg min mL−1, respectively), and time-averaged non-renal clearance (8.12, 7.95, 5.94 and 8.17 mL min−1 kg−1, respectively). AUC values following oral administration were comparable between control and PCMC rats (1520, 1480, 2290 and 1680 μg min mL−1, respectively).