Enhanced paclitaxel bioavailability after oral administration of pegylated paclitaxel prodrug for oral delivery in rats

The bioavailability and pharmacokinetic parameters of paclitaxel in a PEGylated paclitaxel prodrug were studied after the oral administration of paclitaxel (25, 50, 100 mg/kg) and prodrug (87.5, 175, 350 mg/kg) in rats. The area under the plasma concentration-time curve (AUC) of paclitaxel by oral paclitaxel were 836, 1602 and 3076 ng/ml h, which increased dose-dependently (P < 0.006, r = 0.9996). The AUCs of paclitaxel by the oral paclitaxel prodrug were 1646, 3079 and 5998 ng/ml h, also increased dose-dependently (P < 0.003, r = 0.9999). The AUC of paclitaxel by the intravenous administration of paclitaxel (2 mg/kg) was 3992 ng/ml h. The mean absolute bioavailability (AB%) of paclitaxel was 1.6% by the oral administration of paclitaxel. The mean AB% of paclitaxel by the prodrug was 6.3%, which was 3.94-fold higher than the oral paclitaxel. The peak concentration of paclitaxel (C-max) in the dose of 350 mg/kg (50 mg/kg as paclitaxel) of prodrug was 339 ng/ml, which was significantly higher (P < 0.01) than the dose of 50 mg/kg of paclitaxel (104 ng/ml). At the same dose of paclitaxel, the AUC of paclitaxel in the prodrug resulted in a remarkable increase, approximately four-fold compared to the oral paclitaxel. It might be considered that the significantly enhanced bioavailability of paclitaxel by the prodrug, which is water-soluble and easy to permeat through the intestinal mucosa, is due to the avoidance of being inhibited by p-glycoprotein efflux pump in the intestinal mucosa and reduction of metabolism by cytochrome-p-450 (CYP3A) in epitherial cells of small intestine. It appears that the development of oral paclitaxel preparations as a prodrug is possible, which will be more convenient than the IV dosage form. (C) 2004 Elsevier B.V. All rights reserved.