Inhibition of P-Glycoprotein and Multidrug Resistance-Associated Protein 2 Regulates the Hepatobiliary Excretion and Plasma Exposure of Thienorphine and Its Glucuronide Conjugate

Abstract

Thienorphine (TNP) is a novel partial opioid agonist that has completed phase II clinical evaluation as a promising drug candidate for the treatment of opioid dependence. Previous studies have shown that TNP and its glucuronide conjugate (TNP-G) undergo significant bile excretion. The purpose of this study was to investigate the roles of efflux transporters in regulating biliary excretion and plasma exposure of TNP and TNP-G. An ATPase assay suggested that TNP and TNP-G were substrates of P-gp and MRP2, respectively. The in vitro data from rat hepatocytes showed that bile excretion of TNP and TNP-G was regulated by the P-gp and MRP2 modulators. The accumulation of TNP and TNP-G in HepG2 cells significantly increased by the treatment of mdr1a or MRP2 siRNA for P-gp or MRP2 modulation. In intact rats, the bile excretion, and pharmacokinetic profiles of TNP and TNP-G were remarkably changed with tariquidar and probenecid pretreatment, respectively. Tariquidar increased the Cmax and AUC0-t and decreased MRT and T1/2 of TNP, whereas probenecid decreased the plasma exposure of TNP-G and increased its T1/2. Knockdown P-gp and MRP2 function using siRNA significantly increased the plasma exposure of TNP and TNP-G and reduced their mean retention time in mice. These results indicated the important roles of P-gp and MRP2 in hepatobiliary excretion and plasma exposure of TNP and TNP-G. Inhibition of the efflux transporters may affect the pharmacokinetics of TNP and result in a drug-drug interaction between TNP and the concomitant transporter inhibitor or inducer in clinic.

Mechanisms and the clinical relevance of complex drug–drug interactions

“… 105 When Pgp inhibitor tarquidar was coadministered to rats, the C max and AUC of thienorphine increased, while the mean residence time (MRT) and the elimination t 1/2 decreased. 106 The “paradoxically” reduced MRT and elimination t 1/2 of thienorphine was attributed to interrupted enterohepatic circulation through the bile ducts. 106 …”

“… 106 The “paradoxically” reduced MRT and elimination t 1/2 of thienorphine was attributed to interrupted enterohepatic circulation through the bile ducts. 106 …”

“… Notes: a Data from Kong et al 106 The t 1/2 of thienorphine is “paradoxically” increased due to interrupted enterohepatic circulation. Abbreviations: AUC, area under the curve; C max , maximum drug plasma concentration; CL R , renal clearance; DDI, drug–drug interactions; F , oral bioavailability; F g , gut oral bioavailability; PK, pharmacokinetic; Ref, reference; t 1/2 , elimination half time; V T,brain, apparent brain volume distribution; V T, fetus, apparent fetal volume distribution.…”

Breast Cancer Resistance Protein and Multidrug Resistance Protein 2 Determine the Disposition of Esculetin-7-O-Glucuronide and 4-Methylesculetin-7-O-Glucuronide

“…BCRP and MRP2 are likely to excrete compounds with high hydrophilicity such as most conjugation metabolites (glucuronides and sulfates) (An and Morris, 2011;Zheng et al, 2016). The inhibition or deficiency of BCRP and MRP2 decreases the plasma exposure of parent drugs and their metabolites, which could result in reduced efficacy, although these drugs have good absorption characteristics Kong et al, 2016). Transporter (e.g., P-glycoprotein, BCRP, and MRP2) gene knockout models, in which glucuronidation activities remain unaltered, are commonly used in understanding transporter-limited or transportermediated drug absorption, distribution, and excretion (Klaassen and Lu, 2008;Zamek-Gliszczynski et al, 2012.…”

Intake of Molecular Hydrogen in Drinking Water Increases Membrane Transporters, p-Glycoprotein, and Multidrug resistance-associated Protein 2 without Affecting Xenobiotic-metabolizing Enzymes in Rat Liver

“…Induction of phase II detoxifying enzymes and reduction of ROS is most pronounced in the prevention of chemical-induced tissue injuries and carcinogenesis [6]. Phase III membrane transporters include pglycoprotein and multidrug resistance-associated proteins, such as Mrp2/3, which may function to shuttle xenobiotics or their metabolites across cellular membranes and facilitate the excretion of these compounds from the liver into bile (e.g., p-glycoprotein and Mrp2) and blood (e.g., Mrp3) [7][8][9].…”