Effects of cysteine on the pharmacokinetics of docetaxel in rats with protein-calorie malnutrition.

Abstract

The objective of this study is to report the effects of cysteine on the pharmacokinetics of intravenous and oral docetaxel in rats with protein-calorie malnutrition (PCM). The in vivo pharmacokinetics and in vitro hepatic/intestinal metabolism of docetaxel were assessed using control, CC (control with cysteine), PCM and PCMC (PCM with cysteine) rats. The effects of cysteine on the intestinal absorption of docetaxel were further investigated through in vitro transport studies using rat intestine and Caco-2 cell monolayers. The AUCs (the areas under the plasma concentration-time curve from time zero to time infinity) of intravenous docetaxel in PCM rats were significantly greater than in the control rats because of the significant decrease in the hepatic CYP3A. In PCMC rats, the elevated AUCs in PCM rats returned to control levels. The AUC(0-6 h)s of oral docetaxel in PCM rats were significantly smaller than that in the control rats, mainly due to the decrease in gastrointestinal absorption. In CC and PCMC rats, oral cysteine supplement enhanced the gastrointestinal absorption of docetaxel probably via intestinal P-gp inhibition. If the present rat data could be expressed to humans, the alterations in docetaxel absorption and metabolism should be considered in designing a dosage regimen for cancer patients with PCM state after cysteine supplement.