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

Abstract

Background and objectiveP-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.MethodsTwo 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.ResultsIn 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.ConclusionThe present findings extend the available information on tariquidar and provide a basis for future studies involving oral administration of this compound.

The Intestinal Efflux Transporter Inhibition Activity of Xanthones from Mangosteen Pericarp: An In Silico, In Vitro and Ex Vivo Approach

“…The difference in the pharmacokinetics of oral administration between Tariquidar and α-MG was further compared. Data were collected from Matzneller et al [ 30 ] and Li et al [ 31 ]. Results showed that the absolute bioavailability (F) in the solution dosage form was 71.6% for Tariquidar at a dosage of 15 mg/kg and 90.2% for α-MG at a dosage of 20 mg/kg.…”

Effects of P‐gp and Bcrp as brain efflux transporters on the uptake of [18F]FPEB in the murine brain

“…In the present study, we evaluated the effect of the brain efflux transporters on the uptakes of [ 18 F]FPEB in the rat brain. TQD had been considered a highly selective inhibitor of P‐gp, but subsequent studies showed that TQD also inhibits Bcrp (Bankstahl et al, ; Fougère et al, ; Kuntner et al, ; Matzneller et al, ; Robey et al, ). Therefore, in the present study, a combination of pharmacological inhibition and genetic ablation approaches to the efflux transporter systems was used.…”

Alterations in Expression and Function of ABC Family Transporters at Blood-Brain Barrier under Liver Failure and Their Clinical Significances

“…It should be mentioned that the effects of liver failure on the expression and function of ABC transporters at BBB are often dependent on species of ABC transporters, brain regions, duration of liver failure and types of liver failure. Moreover, P-GP and BCRP are also highly expressed in intestine and liver and mediate excretion of their substrate drugs via intestinal wall and bile duct, demonstrating important roles in pharmacokinetics and pharmacology/toxicity of drugs [ 86 , 87 ]. Several reports demonstrated that liver failure downregulated the function and expression of intestinal P-GP [ 88 ], but increased the expression of hepatic BCRP and P-GP [ 89 , 90 ].…”