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 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.


Front Pharmacol


Kong LL,Shen GL,Wang ZY,Zhuang XM,Xiao WB,Yuan M,Gong ZH,Li H




Has Abstract


2016-08-09 00:00:00








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    pub_type: 杂志文章,评审


    authors: Restrepo-Angulo I,Bañuelos C,Camacho J

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  • Eriodictyol Attenuates Myocardial Ischemia-Reperfusion Injury through the Activation of JAK2.

    abstract::Myocardial ischemia-reperfusion (I/R) injury remains the leading risk factor of disability and mortality worldwide. In this study, the myocardial protective effect of eriodictyol (EDT) and the underlying mechanism in an ex vivo model of global myocardial I/R was investigated. After treatment with different concentrati...

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    authors: Li D,Lu N,Han J,Chen X,Hao W,Xu W,Liu X,Ye L,Zheng Q

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  • Metabolomics Reveals Effect of Zishen Jiangtang Pill, a Chinese Herbal Product on High-Fat Diet-Induced Type 2 Diabetes Mellitus in Mice.

    abstract::A Chinese herbal decoction, Zishen Jiangtang Pill (ZJP), has been clinically prescribed to diabetic patients to prevent excessive blood sugar levels for decades. However, the potential mechanisms of this action have not been well investigated. The purpose of this study was to explore the metabolic variations in respon...

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    authors: Chen J,Zheng L,Hu Z,Wang F,Huang S,Li Z,Zheng P,Zhang S,Yi T,Li H

    更新日期:2019-03-19 00:00:00

  • Periplaneta americana Extracts Accelerate Liver Regeneration via a Complex Network of Pathways.

    abstract::Successful recovery from hepatectomy is partially contingent upon the rate of residual liver regeneration. The traditional Chinese medicines known as Periplaneta americana extracts (PAEs) positively influence wound healing by promoting tissue repair. However, the effect of PAEs on liver regeneration is unknown. We use...

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    authors: Zou Y,Zhang M,Zeng D,Ruan Y,Shen L,Mu Z,Zou J,Xie C,Yang Z,Qian Z,Xu R,Li S,Kang Q,Zou H,Zhao S,Liu L,Wang K,Wang X,Zhang X

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  • Growth Pattern in Chinese Children With 5α-Reductase Type 2 Deficiency: A Retrospective Multicenter Study.

    abstract:Background:5α-reductase type 2 deficiency (5αRD) is an autosomal recessive hereditary disease of the group of 46, XY disorders of sex development (DSD). Objective:To study the growth pattern in Chinese pediatric patients with 5αRD. Subjects:Data were obtained from 141 patients with 5αRD (age: 0-16 years old) who visi...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章


    authors: Zhao X,Song Y,Chen S,Wang X,Luo F,Yang Y,Chen L,Chen R,Chen H,Su Z,Wu D,Gong C

    更新日期:2019-03-15 00:00:00

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    abstract::The objective of this study was to test the hypothesis that serotonin O-sulphate (5-HT-SO4) could be quantified in human plasma using modern liquid chromatography-mass spectrometry (LC-MS) method as well as develop and validate that method. First, a suitable LC-MS method for detection of 5-HT-SO4 in human plasma sampl...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章


    authors: Lozda R,Purviņš I

    更新日期:2014-04-08 00:00:00

  • Screening and Identification of Cardioprotective Compounds From Wenxin Keli by Activity Index Approach and in vivo Zebrafish Model.

    abstract::Wenxin Keli (WXKL) is a widely used Chinese botanical drug for the treatment of arrhythmia, which is consisted of four herbs and amber. In the present study, we analyzed the chemical composition of WXKL using liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) to tentatively identify 71 comp...

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    authors: Liu H,Chen X,Zhao X,Zhao B,Qian K,Shi Y,Baruscotti M,Wang Y

    更新日期:2018-11-13 00:00:00

  • A Comprehensive Strategy to Evaluate Compatible Stability of Chinese Medicine Injection and Infusion Solutions Based on Chemical Analysis and Bioactivity Assay.

    abstract::Stability of traditional Chinese medicine injection (TCMI) is an important issue related with its clinical application. TCMI is composed of multi-components, therefore, when evaluating TCMI stability, several marker compounds cannot represent global components or biological activities of TCMI. Till now, when evaluatin...

    journal_title:Frontiers in pharmacology

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    authors: Li JP,Liu Y,Guo JM,Shang EX,Zhu ZH,Zhu KY,Tang YP,Zhao BC,Tang ZS,Duan JA

    更新日期:2017-11-15 00:00:00

  • Development of a Hyaluronic Acid-Based Nanocarrier Incorporating Doxorubicin and Cisplatin as a pH-Sensitive and CD44-Targeted Anti-Breast Cancer Drug Delivery System.

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    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章


    authors: Yu T,Li Y,Gu X,Li Q

    更新日期:2020-08-28 00:00:00

  • SARS-CoV-2 Treatment Approaches: Numerous Options, No Certainty for a Versatile Virus.

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    pub_type: 杂志文章,评审


    authors: Iacob S,Iacob DG

    更新日期:2020-08-26 00:00:00

  • Capsaicin-Induced Skin Desensitization Differentially Affects A-Delta and C-Fiber-Mediated Heat Sensitivity.

    abstract::Localized neuropathic pain can be relieved following the topical application of high-concentration capsaicin. This clinical effect is thought to be related to the temporary desensitization of capsaicin- and heat-sensitive epidermal nociceptors. The objective of the present study was to examine whether the changes in t...

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    authors: van Neerven SGA,Mouraux A

    更新日期:2020-05-19 00:00:00

  • Artificial Intelligence-Based Multiclass Classification of Benign or Malignant Mucosal Lesions of the Stomach.

    abstract::Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide. It takes some time from chronic gastritis to develop in GC. Early detection of GC will help patients obtain timely treatment. Understanding disease evolution is crucial for the prevention and treatment of GC. Here, we present a convolu...

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    pub_type: 杂志文章


    authors: Ma B,Guo Y,Hu W,Yuan F,Zhu Z,Yu Y,Zou H

    更新日期:2020-10-02 00:00:00

  • Managed Entry Agreements for Oncology Drugs: Lessons from the European Experience to Inform the Future.

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    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章


    authors: Pauwels K,Huys I,Vogler S,Casteels M,Simoens S

    更新日期:2017-04-04 00:00:00

  • Hupresin Retains Binding Capacity for Butyrylcholinesterase and Acetylcholinesterase after Sanitation with Sodium Hydroxide.

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    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章


    authors: Onder S,David E,Tacal O,Schopfer LM,Lockridge O

    更新日期:2017-10-10 00:00:00

  • ABT-263 Reduces Hypertrophic Scars by Targeting Apoptosis of Myofibroblasts.

    abstract::Background: Inhibiting proliferation and inducing apoptosis of myofibroblasts is becoming one of the promising and effective ways to treat hypertrophic scar. ABT-263, as an orally bioavailable BCL-2 family inhibitor, has showed great antitumor characteristics by targeting tumor cell apoptosis. The objective of this st...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章


    authors: Yang X,Xiao Y,Zhong C,Shu F,Xiao S,Zheng Y,Xia Z

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  • The Ecto-5'-Nucleotidase/CD73 Inhibitor, α,β-Methylene Adenosine 5'-Diphosphate, Exacerbates Carrageenan-Induced Pleurisy in Rat.

    abstract::The ecto-5'-nucleotidase (ecto-5'NT/CD73) represents a crucial enzyme for endogenous adenosine generation. Several findings have shown that CD73 plays an important role in regulating vascular permeability and immune cell function. Adenosine 5'-(α,β-methylene)diphosphate (APCP) is a CD73 inhibitor, widely used as pharm...

    journal_title:Frontiers in pharmacology

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    authors: Caiazzo E,Morello S,Carnuccio R,Ialenti A,Cicala C

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  • The Mechanisms of Traditional Chinese Medicine Underlying the Prevention and Treatment of Parkinson's Disease.

    abstract::Parkinson's disease (PD), characterized with bradykinesia, static tremor, rigidity and disturbances in balance, is the second most common neurodegenerative disorder. Along with the largely aging population in the world, the incidence is increasing year by year, which imposes the negative impacts on patients, their fam...

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    authors: Li X,Zhang Y,Wang Y,Xu J,Xin P,Meng Y,Wang Q,Kuang H

    更新日期:2017-09-19 00:00:00

  • The Reproductive Toxicity of Mequindox in a Two-Generation Study in Wistar Rats.

    abstract::Mequindox (MEQ), belonging to quinoxaline-di-N-oxides (QdNOs), has been extensively used as a synthetic antibacterial agent. To evaluate the reproductive toxicity of MEQ, different concentrations of MEQ were administered to Wistar rats by feeding diets containing 0, 25, 55, 110, and 275 mg/kg, respectively. Each group...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章


    authors: Liu Q,Lei Z,Wu Q,Awais I,Shabbir MAB,Ahmed S,Fatima Z,Wang X,Pan Y,Xie S,Yuan Z

    更新日期:2018-08-17 00:00:00

  • Identification of Epigallocatechin-3- Gallate as an Inhibitor of Phosphoglycerate Mutase 1.

    abstract::Targeting metabolic enzymes is believed to provide new therapeutic opportunities for cancer therapy. Phosphoglycerate mutase 1 (PGAM1) is a glycolytic enzyme that importantly coordinates glycolysis, pentose phosphate pathway (PPP) flux and serine biosynthesis in cancer cells and hence gains increasing interest of inhi...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章


    authors: Li X,Tang S,Wang QQ,Leung EL,Jin H,Huang Y,Liu J,Geng M,Huang M,Yuan S,Yao XJ,Ding J

    更新日期:2017-05-30 00:00:00

  • Corrigendum: Furanodiene Induces Extrinsic and Intrinsic Apoptosis in Doxorubicin-Resistant MCF-7 Breast Cancer Cells via NF-κB-Independent Mechanism.

    abstract::[This corrects the article on p. 648 in vol. 8, PMID: 28959205.]. ...

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    pub_type: 杂志文章,已发布勘误


    authors: Zhong ZF,Yu HB,Wang CM,Qiang WA,Wang SP,Zhang JM,Yu H,Cui L,Wu T,Li DQ,Wang YT

    更新日期:2017-12-18 00:00:00

  • PACAP and VIP Inhibit the Invasiveness of Glioblastoma Cells Exposed to Hypoxia through the Regulation of HIFs and EGFR Expression.

    abstract::Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) through the binding of vasoactive intestinal peptide receptors (VIPRs), perform a wide variety of effects in human cancers, including glioblastoma multiforme (GBM). This tumor is characterized by extensive areas of hypox...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章


    authors: Maugeri G,D'Amico AG,Reitano R,Magro G,Cavallaro S,Salomone S,D'Agata V

    更新日期:2016-05-31 00:00:00

  • Betulinic Acid Enhances the Viability of Random-Pattern Skin Flaps by Activating Autophagy.

    abstract::Random-pattern skin flap replantation is commonly used to repair skin defects during plastic and reconstructive surgery. However, flap necrosis due to ischemia and ischemia-reperfusion injury limits clinical applications. Betulinic acid, a plant-derived pentacyclic triterpene, may facilitate flap survival. In the pres...

    journal_title:Frontiers in pharmacology

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    authors: Li J,Bao G,ALyafeai E,Ding J,Li S,Sheng S,Shen Z,Jia Z,Lin C,Zhang C,Lou Z,Xu H,Gao W,Zhou K

    更新日期:2019-09-13 00:00:00

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    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章


    authors: Bröer A,Fairweather S,Bröer S

    更新日期:2018-07-19 00:00:00

  • Anti-Methicillin-Resistant Staphylococcus aureus Nanoantibiotics.

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    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章,评审


    authors: Labruère R,Sona AJ,Turos E

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  • Short-Term Efficacy and Tolerability of Paroxetine Versus Placebo for Panic Disorder: A Meta-Analysis of Randomized Controlled Trials.

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    journal_title:Frontiers in pharmacology



    authors: Zhang B,Wang C,Cui L,Gao J,Wang C,Tan X,Fang S

    更新日期:2020-03-31 00:00:00

  • ATC-NLSP: Prediction of the Classes of Anatomical Therapeutic Chemicals Using a Network-Based Label Space Partition Method.

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    pub_type: 杂志文章


    authors: Wang X,Wang Y,Xu Z,Xiong Y,Wei DQ

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  • Chijabyukpi-Tang Inhibits Pro-Inflammatory Cytokines and Chemokines via the Nrf2/HO-1 Signaling Pathway in TNF-α/IFN-γ-Stimulated HaCaT Cells and Ameliorates 2,4-Dinitrochlorobenzene-Induced Atopic Dermatitis-Like Skin Lesions in Mice.

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    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章


    authors: Lee JH,Lim JY,Jo EH,Noh HM,Park S,Park MC,Kim DK

    更新日期:2020-07-07 00:00:00

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    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章


    authors: He S,Guo Y,Zhao J,Xu X,Wang N,Liu Q

    更新日期:2020-04-03 00:00:00

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    abstract::Sigma-1 receptors (S1R) and sigma-2 receptors (S2R) may modulate nociception without the liabilities of opioids, offering a promising therapeutic target to treat pain. The purpose of this study was to investigate the in vivo analgesic and anti-allodynic activity of two novel sigma receptor antagonists, the S1R-selecti...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章


    authors: Cirino TJ,Eans SO,Medina JM,Wilson LL,Mottinelli M,Intagliata S,McCurdy CR,McLaughlin JP

    更新日期:2019-06-14 00:00:00

  • Role of connexins in human congenital heart disease: the chicken and egg problem.

    abstract::Inborn cardiac diseases are among the most frequent congenital anomalies and are the main cause of death in infants within the first year of age in industrialized countries when not adequately treated. They can be divided into simple and complex cardiac malformations. The former ones, for instance atrial and ventricul...

    journal_title:Frontiers in pharmacology

    pub_type: 杂志文章


    authors: Salameh A,Blanke K,Daehnert I

    更新日期:2013-06-03 00:00:00