Pharmacokinetics of the P-gp Inhibitor Tariquidar in Rats After Intravenous, Oral, and Intraperitoneal Administration

Background and objective: P-glycoprotein (P-gp), a transmembrane transporter expressed at the blood–brain barrier, restricts the distribution of diverse central nervous system-targeted drugs from blood into brain, reducing their therapeutic efficacy. The third-generation P-gp inhibitor tariquidar (XR9576) was shown to enhance brain distribution of P-gp substrate drugs in humans. Oral bioavailability of tariquidar was found to be low in humans requiring the compound to be administered intravenously, which hinders a broader clinical use. The objective of the present study was to investigate the plasma pharmacokinetics of tariquidar in rats after single intravenous, oral, and intraperitoneal administration. Methods: Two different tariquidar formulations (A and B) were used, both at a dosage of 15 mg/kg, respectively. Formulation A was a solution and formulation B was a microemulsion which was previously shown to improve the oral bioavailability of the structurally related P-gp inhibitor elacridar in mice. Results: In contrast to human data, the present study found a high bioavailability of tariquidar in rats after oral dosing. Oral bioavailability was significantly higher (p = 0.032) for formulation B (86.3%) than for formulation A (71.6%). After intraperitoneal dosing bioavailability was 91.4% for formulation A and 99.6% for formulation B. Conclusion: The present findings extend the available information on tariquidar and provide a basis for future studies involving oral administration of this compound.