Impact of P-Glycoprotein on Intestinal Absorption of an Inhibitor of Apoptosis Protein Antagonist in Rats: Mechanisms of Nonlinear Pharmacokinetics and Food Effects

Abstract

Purpose: This study was designed to investigate the effects of P-glycoprotein (P-gp) expressed in the intestine on the nonlinear pharmacokinetics (PK) of T-3256336, an inhibitor of apoptosis protein inhibitor, and food effects on its bioavailability in rats.

Methods: To investigate the factors that contribute to nonlinear PK of T-3256336 in the intestine and liver, rats double-cannulated in the portal vein and femoral artery (PS rats) were used. F_aF_g (F_a, absorption ratio; F_g, intestinal availability) and hepatic availability (F_h) were simultaneously evaluated based on the difference between the portal and systemic blood area under the concentration-time curve (AUC). Elacridar was used as a P-gp inhibitor to assess the impact of P-gp on the intestinal absorption.

Results: After oral administration of T-3256336 to PS rats at 3 and 30 mg/kg, F_aF_g value increased with dose escalation, whereas F_h value was nearly constant. Moreover, co-administration of elacridar resulted in a 5-fold increase in the F_aF_g value at 3 mg/kg. The AUC value of T-3256336 under fed conditions was 3-fold lower than that under fasted conditions. This food effect on the oral bioavailability (BA) was reduced by concomitant administration of elacridar.

Conclusion: P-gp expressed in the intestine would cause nonlinear PK and a food effect on BA of T-3256336 in rats.

Keywords: Absorption; Effulx transporters; Food effect; Inhibitor of apoptosis protein; Nonlinear pharmacokinetics.