Evaluation of the Role of P-glycoprotein (P-gp)-Mediated Efflux in the Intestinal Absorption of Common Substrates with Elacridar, a P-gp Inhibitor, in Rats.

Background And Objectives: P-glycoprotein (P-gp) has been shown previously to contribute to the intestinal absorption of verapamil, diltiazem, tacrolimus, colchicine and indinavir in situ; however, its contribution in vivo is unknown. The present study aimed to evaluate the in vivo involvement of P-gp using elacridar as its inhibitor to distinguish the contribution of P-gp from cytochrome P450 (CYP) 3A.

Methods: Fexofenadine (5 mg/kg) and buspirone (1 mg/kg) were used as probe substrates of P-gp and CYP3A, respectively. Each dual substrate (1 or 2 mg/kg) was orally administered to rats after elacridar pre-treatment (3 mg/kg). Additionally, verapamil, diltiazem or tacrolimus was orally co-administered with fexofenadine.

Results: Elacridar drastically increased the area under the plasma concentration-time curve (AUC) of oral fexofenadine by 8.6-fold; however, it did not affect the AUC of oral buspirone. Therefore, elacridar inhibited P-gp without affecting CYP3A. The absorption of oral verapamil, diltiazem and tacrolimus was not influenced by elacridar pre-treatment, and the increase in the AUC of fexofenadine was approximately 3-fold when co-administered with each substrate; the minimal effect of elacridar was attributable to the limited contribution of P-gp but not to their self-inhibition against the transporter. Conversely, elacridar significantly increased the AUC of colchicine (5.3-fold) and indinavir (2.0-fold), indicating that P-gp contributes to their absorption.

Conclusions: Elacridar is useful for distinguishing the contribution of P-gp from CYP3A to the absorption of drugs in rats. The in vivo contribution of P-gp is minimal for high permeable compounds owing to their fraction absorbed of nearly 1.0.