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

In rats with protein-calorie malnutrition (PCM, 5% caseine diet for 4 weeks ), hepatic cytochrome P450 levels suppressed markedly and cytochrome P450 m RNAs decreased significantly compared with those in control rats (23% casei ne diet for 4 weeks), however, the values completely (or partially) returne d to control levels by a week (from fourth week) of cysteine supplementatio n (rats with PCMC) (Cho, Kim et al., Arch. Biochem. Biophys. 1999, 372: 150 -158). The formation of aglycone metabolites of adriamycin and adriamycinol , M3 and M4, respectively, seemed to be induced (Lee and Lee, Res. Commun. Mol. Pathol. Pharmacol. 1999, 105: 87-96) by pretreatment with dexamethason e (possibly by hepatic cytochrome P450 RL 33/cDEX, Komori and Oda, J. Bioch em. 1994, 116: 114-120) in rats. Adriamycin, 16 mg/kg, was administered int ravenously in 1-min to control rats and rats with PCM and PCMC. In rats wit h PCM, the plasma concentrations of adriamycin was higher (the area under t he plasma concentration-time curve from time zero to 12 hr, AUC(0-12 hr), t ended to be higher) and 24-hr urinary excretion of M3 (including its 'conju gates') seemed to increase than those in control rats, suggested that the f ormation of M3 was inhibited in rats with PCM. In rats with PCMC, the plasm a concentrations of adriamycin were lower (the AUC(0-12 hr) was significant ly smaller) and 24-hr urinary excretion of M3 (including its 'conjugates') were significantly greater than those in rats with PCM, suggested that the formation of M3 increased significantly by cysteine supplementation by rest oring the enzyme system(s) that metabolize adriamycin to M3, The altered ph armacokinetic parameters of adriamycin mentioned above in rats with PCM ret urned to greater than those of control rats after cysteine supplementation (rats with PCMC). Above data suggested that other hepatic cytochrome P450 i sozyme(s) which catalyze(s) the formation of M3 from adriamycin could be in duced by cysteine supplementation.