Low systemic exposure of oral docetaxel in mice resulting from extensive first-pass metabolism is boosted by...

P-glycoprotein seems to be the most important factor limiting the oral absorption of paclitaxel. We have now explored the mechanisms responsible for the low oral bioavailability of docetaxel, a structurally related taxane drug. The recovery of 33% of oxidative metabolites and only 39% of unchanged drug in the feces of FVB wild-type mice receiving 10 mg/kg of oral docetaxel indicates that the major part of the oral dose has been absorbed. The feces and bile of mice receiving 10 mg/kg of i.v. docetaxel contained large amounts of metabolites and only minor quantities of unchanged drug, highlighting the importance of metabolism as an elimination route for this drug. In wild-type and P-glycoprotein knockout mice, dose escalation of p.o. administered docetaxel from 10 to 30 mg/kg resulted in a more than proportional increase in plasma levels, which suggested saturation of first-pass metabolism. Moreover, coadministration of 12.5 mg/kg of the HIV protease inhibitor ritonavir, also a strong inhibitor of cytochrome P4503A4 with only minor P-glycoprotein inhibiting properties, increased the plasma levels after oral docetaxel by 50-fold. In vitro transport studies across monolayers of LLC-PK1 cells (parental and transduced with MDR1 or Mdr1a) suggested that docetaxel is a weaker substrate for P-glycoprotein than paclitaxel is. In conclusion, docetaxel is well absorbed from the gut lumen in mice despite the presence of P-glycoprotein in the gut wall. Subsequent first-pass extraction is the most important factor determining its low bioavailability. The inhibition of docetaxel metabolism by ritonavir provides an interesting strategy to improve the systemic exposure of oral docetaxel.