Effect of efavirenz on intestinal p-glycoprotein and hepatic p450 function in rats

P-glycoprotein (P-gp) and cytochrome P450 (P450) affect drug disposition. Efavirenz (EFV) is an anti-HIV drug used in combination. Since most anti-HIV medications are substrate and modulators of P-gp and/or P450, we investigated the effects of EFV on intestinal P-gp and hepatic P450 function to predict drug interactions.

(i) The effect of EFV on rat intestinal P-gp function was studied on everted gut sacs and in situ intestinal perfusion. EFV was orally administered (150 mg/kg) for 6 days. Then, rhodamine 123 was used as a P-gp substrate and verapamil as an inhibitor. P-gp function was evaluated by the difference between rhodamine 123 transport with and without verapamil. (ii) The effect of EFV on rat hepatic P450 metabolism was investigated using hepatic microsomes, prepared from rats pretreated or not with EFV.

In everted gut sacs, P-gp function was not modified and in the in situ intestinal perfusion, rhodamine 123 clearance was not affected by EFV. Concentrations of the metabolites, 1-OH midazolam and 4-OH midazolam were higher in EFV pretreated rats than those in the control group.

EFV should not modify intestinal absorption of co-administered substrates of P-gp, but could decrease plasma concentrations of co-administered drugs metabolized by P450.