Paclitaxel (PTX) is an anticancer agent that is used to treat many cancers but it has a very low\noral bioavailability due, at least in part, to the drug efflux transporter, P-glycoprotein (P-gp). Therefore,\nthis study was performed to enhance oral bioavailability of PTX. In this study, we investigated the\neffects of several piperazine derivatives on P-gp function in vitro. Compound 4 was selected as the\nmost potent P-gp inhibitor from the in vitro results for examining the pharmacokinetic (PK) changes\nof PTX in rats. Compound 4 increased the AUCinf of PTX without alterations in the Cmax value.\nThe elimination half-life was extended and the oral clearance decreased. Additionally, the Tmax was\ndelayed or widened in the treatment groups. Therefore, the bioavailability (BA) of PTX was improved\n2.1-fold following the co-administration of 5 mg/kg of the derivative. A piperazine derivative,\ncompound 4, which was confirmed as a substantial P-gp inhibitor in vitro increased the BA of PTX\nup to 2-fold by a lingering absorption, in part due to inhibition of intestinal P-gp and a low oral\nclearance of PTX. These results suggest that co-administering compound 4 may change the PK profile\nof PTX by inhibiting P-gp activity in the body.
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