Effects of experimental hyperlipidaemia on the pharmacokinetics of docetaxel in rats

Hyperlipidaemia correlates with an increased risk of occurrence of various cancers. In this study, the effects of hyperlipidaemia on the pharmacokinetics of docetaxel, a member of the taxane class of anti-cancer drugs, were investigated in rats with experimental hyperlipidaemia; we focused on the alterations in docetaxel metabolism and plasma distribution. Docetaxel (5 mg/kg intravenously (i.v.) and 40 mg/kg per oral (p.o.)) was administered to control rats and rats with poloxamer-407 (P-407)-induced hyperlipidaemia (1 g/kg, intraperitoneally). In vitro studies were conducted on hepatic metabolism in S9 fractions and plasma protein binding using the ultrafiltration method. Hyperlipidaemia dramatically increased the area under the plasma concentration-time curve from time 0 to infinity (AUC(0-∞)) of docetaxel after i.v. (1.86-fold) or p.o. (10.8-fold) administration and decreased total body clearance (0.574-fold) and apparent volume of distribution at steady state (0.615-fold) of docetaxel after i.v. administration. Compared with the control rats, the metabolism of docetaxel by hepatic S9 fractions and the unbound fraction in the plasma in the hyperlipidaemic rats were decreased, i.e., by 20.1 and 79.8%, respectively. In conclusion, the alterations in docetaxel pharmacokinetics in rats with P-407-induced hyperlipidaemia may be due, at least in part, to a decrease in hepatic metabolism and the unbound fraction of docetaxel in the plasma. These findings have potential therapeutic implications for predicting human pharmacokinetic responses to hyperlipidaemia.