Effect of maceligan on the systemic exposure of paclitaxel: in vitro and in vivo evaluation.

This study investigated the effect of macelignan on the P-glycoprotein-mediated drug efflux as well as CYP3A4-mediated drug metabolism and subsequently its in vivo implication on the bioavailability of paclitaxel. The inhibition effect of macelignan on the CYP3A4-mediated metabolism was negligible over the concentration range of 0.01-100muM in rat liver microsome while approximately 33% inhibition was observed at 100muM in human liver microsome, implying that the interaction of macelignan with CYP3A4 might be insignificant at the physiologically achievable concentrations. In contrast, macelignan (20muM) increased the cellular accumulation of paclitaxel by approximately 1.7-fold in NCI/ADR-RES cells overexpressing P-gp, while it did not alter the cellular accumulation of paclitaxel in OVCAR-8 cells lacking P-gp. The effect of macelignan on the systemic exposure of paclitaxel was also examined in rats after the intravenous and oral administration of paclitaxel in the presence and the absence of macelignan. The concurrent use of macelignan significantly (p<0.05) enhanced the oral exposure of paclitaxel in rats while it did not affect the intravenous pharmacokinetics of paclitaxel, implying that macelignan might be more effective to improve the intestinal absorption rather than reducing hepatic elimination. In conclusion, macelignan appeared to be effective to improve the cellular accumulation as well as oral exposure of paclitaxel mainly via the inhibition of P-gp-mediated cellular efflux, suggesting that the concomitant use of macelignan may provide a therapeutic benefit in improving the anticancer efficacy of paclitaxel.