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Enhanced paclitaxel bioavailability after oral administration of paclitaxel or prodrug to rats pretreated with quercetin

2004; Elsevier BV; Volume: 57; Issue: 2 Linguagem: Inglês

10.1016/j.ejpb.2003.11.002

1873-3441

Jun‐Shik Choi, Byung-Wok Jo, Youn‐Chul Kim,

Pharmacogenetics and Drug Metabolism

The aim of this study was to investigate the effect of quercetin on the bioavailability of paclitaxel after the oral administration of paclitaxel or a prodrug to rats pretreated with quercetin. Paclitaxel (40 mg/kg) and prodrug (280 mg/kg, 40 mg/kg as the paclitaxel) were administered orally to rats pretreated with quercetin (2, 10, 20 mg/kg). The plasma concentrations of paclitaxel pretreated with quercetin were increased significantly (P<0.01, for paclitaxel; P<0.05, for prodrug) compared to the control. The areas under the plasma concentration–time curve (AUC) and the peak concentrations (Cmax) of paclitaxel pretreated with quercetin were significantly higher (P<0.01) than the control. The half-life (t1/2) and mean residence times were significantly (P<0.05) longer compared to the control. The absolute bioavailability (AB%) of paclitaxel pretreated with quercetin was significantly higher (P<0.01) than the control. The AUC of paclitaxel after administration of the prodrug to rats pretreated with quercetin was significantly (P<0.05) higher than the prodrug control. The relative bioavailability of paclitaxel after administration of the prodrug to rats pretreated with quercetin was 1.25- to 2.02-fold higher than the prodrug control. The AB% of paclitaxel was increased significantly (P<0.05) by quercetin from 8.0 to 10.1 and 16.2%. The bioavailability of paclitaxel administered as a prodrug with or without pretreatment of quercetin was remarkably higher than the control. AUC, AB% and Cmax of paclitaxel after administration of the paclitaxel or prodrug pretreated with quercetin for 3 days were much higher than those administered after 20 min. It might have resulted from the physicochemical properties of the prodrug, which is a water-soluble compound and passes through the gastrointestinal mucosa more easily than paclitaxel without obstruction of P-gp and cytochrome P-450 in the gastrointestinal mucosa. It seems that the development of oral paclitaxel preparations as a prodrug or with quercetin is feasible, which is more convenient than the i.v. dosage forms.