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

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 thi...

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Autores principales: Kong, Ling-Lei, Shen, Guo-Lin, Wang, Zhi-Yuan, Zhuang, Xiao-Mei, Xiao, Wei-Bin, Yuan, Mei, Gong, Ze-Hui, Li, Hua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4977286/
https://www.ncbi.nlm.nih.gov/pubmed/27555820
http://dx.doi.org/10.3389/fphar.2016.00242
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author Kong, Ling-Lei
Shen, Guo-Lin
Wang, Zhi-Yuan
Zhuang, Xiao-Mei
Xiao, Wei-Bin
Yuan, Mei
Gong, Ze-Hui
Li, Hua
author_facet Kong, Ling-Lei
Shen, Guo-Lin
Wang, Zhi-Yuan
Zhuang, Xiao-Mei
Xiao, Wei-Bin
Yuan, Mei
Gong, Ze-Hui
Li, Hua
author_sort Kong, Ling-Lei
collection PubMed
description 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 C(max) and AUC(0-t) and decreased MRT and T(1/2) of TNP, whereas probenecid decreased the plasma exposure of TNP-G and increased its T(1/2). 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.
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spelling pubmed-49772862016-08-23 Inhibition of P-Glycoprotein and Multidrug Resistance-Associated Protein 2 Regulates the Hepatobiliary Excretion and Plasma Exposure of Thienorphine and Its Glucuronide Conjugate Kong, Ling-Lei Shen, Guo-Lin Wang, Zhi-Yuan Zhuang, Xiao-Mei Xiao, Wei-Bin Yuan, Mei Gong, Ze-Hui Li, Hua Front Pharmacol Pharmacology 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 C(max) and AUC(0-t) and decreased MRT and T(1/2) of TNP, whereas probenecid decreased the plasma exposure of TNP-G and increased its T(1/2). 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. Frontiers Media S.A. 2016-08-09 /pmc/articles/PMC4977286/ /pubmed/27555820 http://dx.doi.org/10.3389/fphar.2016.00242 Text en Copyright © 2016 Kong, Shen, Wang, Zhuang, Xiao, Yuan, Gong and Li. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Kong, Ling-Lei
Shen, Guo-Lin
Wang, Zhi-Yuan
Zhuang, Xiao-Mei
Xiao, Wei-Bin
Yuan, Mei
Gong, Ze-Hui
Li, Hua
Inhibition of P-Glycoprotein and Multidrug Resistance-Associated Protein 2 Regulates the Hepatobiliary Excretion and Plasma Exposure of Thienorphine and Its Glucuronide Conjugate
title Inhibition of P-Glycoprotein and Multidrug Resistance-Associated Protein 2 Regulates the Hepatobiliary Excretion and Plasma Exposure of Thienorphine and Its Glucuronide Conjugate
title_full Inhibition of P-Glycoprotein and Multidrug Resistance-Associated Protein 2 Regulates the Hepatobiliary Excretion and Plasma Exposure of Thienorphine and Its Glucuronide Conjugate
title_fullStr Inhibition of P-Glycoprotein and Multidrug Resistance-Associated Protein 2 Regulates the Hepatobiliary Excretion and Plasma Exposure of Thienorphine and Its Glucuronide Conjugate
title_full_unstemmed Inhibition of P-Glycoprotein and Multidrug Resistance-Associated Protein 2 Regulates the Hepatobiliary Excretion and Plasma Exposure of Thienorphine and Its Glucuronide Conjugate
title_short Inhibition of P-Glycoprotein and Multidrug Resistance-Associated Protein 2 Regulates the Hepatobiliary Excretion and Plasma Exposure of Thienorphine and Its Glucuronide Conjugate
title_sort inhibition of p-glycoprotein and multidrug resistance-associated protein 2 regulates the hepatobiliary excretion and plasma exposure of thienorphine and its glucuronide conjugate
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4977286/
https://www.ncbi.nlm.nih.gov/pubmed/27555820
http://dx.doi.org/10.3389/fphar.2016.00242
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