Oral etoposide and zosuquidar bioavailability in rats: Effect of co-administration and in vitro-in vivo correlation of P-glycoprotein inhibition

P-glycoprotein inhibitors, like zosuquidar, have widely been used to study the role of P-glycoprotein in oral absorption. Still, systematic studies on the inhibitor dose-response relationship on intestinal drug permeation are lacking. In the present study, we investigated the effect of 0.79 nM-2.5 mu M zosuquidar on etoposide permeability across Caco-2 cell monolayers. We also investigated etoposide pharmacokinetics after oral or IV administration to Sprague Dawley rats with co-administration of 0.063-63 mg/kg zosuquidar, as well as the pharmacokinetics of zosuquidar itself. Oral zosuquidar bioavailability was 2.6-4.2%, while oral etoposide bioavailability was 5.5 +/- 0.9%, which increased with increasing zosuquidar doses to 35 +/- 5%. The intestinal zosuquidar concentration required to induce a half-maximal increase in bioavailability was estimated to 180 mu M. In contrast, the IC50 of zosuquidar on etoposide permeability in vitro was only 5-10 nM, and a substantial in vitro-in vivo discrepancy of at least four orders of magnitude was thereby identified. Overall, the present study provides valuable insights for future formulation development that applies fixed dose combinations of P-glycopmtein inhibitors to increase the absorption of poorly permeable P-glycoprotein substrate drugs.

Automated summary

This study investigated the impact of zosuquidar on the permeability and bioavailability of etoposide, revealing a significant discrepancy in effectiveness between in vitro and in vivo settings. The findings offer crucial insights for future formulation development to enhance the absorption of poorly permeable P-glycoprotein substrate drugs.