NTCP - 抑制剂myrcludex B：对胆汁酸配置和替诺福韦药代动力学

StephenW

Clin Pharmacol Ther. 2017 May 24. doi: 10.1002/cpt.744. [Epub ahead of print]
The NTCP - inhibitor myrcludex B: Effects on bile acid disposition and tenofovir pharmacokinetics.
Blank A1,2, Eidam A1,2, Haag M3,4, Hohmann N1,2, Burhenne J1,2, Schwab M3,4,5,6, van de Graaf SFJ7, Meyer MR1,8, Maurer HH8, Meier K1,2, Weiss J1,2, Bruckner T9, Alexandrov A10, Urban S2,11, Mikus G1,2, Haefeli WE1,2.
Author information

1    Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
2    German Center for Infection Research (DZIF), Heidelberg Partner Site, Im Neuenheimer Feld 324, 69120, Heidelberg, Germany.
3    Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, University of Tübingen, Auerbachstraße 112, 70376, Stuttgart, Germany.
4    German Center for Infection Research (DZIF), Tübingen Partner Site, E.-Aulhorn-Str. 6, 72076, Tübingen, Germany.
5    Department of Clinical Pharmacology, University Hospital Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany.
6    Department of Pharmacy and Biochemistry, University of Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany.
7    Tytgat Institute for Liver and Intestinal Research & Department of Gastroenterology & Hepatology, Academic Medical Center, Meibergdreef 69-71, 1105, BK, Amsterdam, The Netherlands.
8    Experimental and Clinical Toxicology, Saarland University, Kirrberger Str. - Geb. 46, 66421, Homburg, Germany.
9    Institute of Medical Biostatistics and Medical Informatics, Heidelberg University Hospital, Im Neuenheimer Feld 305, 69120, Heidelberg, Germany.
10    Myr GmbH, Weinbergsweg 66, 61348, Bad Homburg, Germany.
11    Department of Infectious Diseases, Molecular Virology, Heidelberg University Hospital, Im Neuenheimer Feld 345, 69120, Heidelberg, Germany.

Abstract

Myrcludex B acts as a hepatitis B and D virus entry inhibitor blocking the sodium taurocholate co-transporting polypeptide (SLC10A1). We investigated effects of myrcludex B on plasma bile acid disposition, tenofovir pharmacokinetics, and perpetrator characteristics on cytochrome P450 (CYP) 3A. Twelve healthy volunteers received 300 mg tenofovir disoproxil fumarate orally and 10 mg subcutaneous myrcludex B. Myrcludex B increased total plasma bile acid exposure 18.2-fold without signs of cholestasis. The rise in conjugated bile acids was up to 123-fold (taurocholic acid). Co-administration of tenofovir with myrcludex B revealed no relevant changes in tenofovir pharmacokinetics. CYP3A activity slightly but significantly decreased by 29% during combination therapy. Myrcludex B caused an asymptomatic but distinct rise in plasma bile acid concentrations and had no relevant impact on tenofovir pharmacokinetics. Changes in CYP3A activity might be due to alterations in bile acid signaling. Long-term effects of elevated bile acids will require critical evaluation. This article is protected by copyright. All rights reserved.

© 2017 American Society for Clinical Pharmacology and Therapeutics.
KEYWORDS:

Cytochrome P450 3A4; Drug interactions; Hepatitis B; Hepatitis D; Midazolam clearance; Pharmacokinetics; Sodium taurocholate co-transporting polypeptide (SLC10A1)

PMID:
    28543042
DOI:
    10.1002/cpt.744

StephenW

Clin Pharmacol Ther。 2017年5月24日。doi：10.1002 / cpt.744。 [提前印刷]
NTCP - 抑制剂myrcludex B：对胆汁酸配置和替诺福韦药代动力学的影响。
空白A1,2，Eidam A1,2，Haag M3,4，Hohmann N1,2，Burhenne J1,2，Schwab M3,4,5,6，van de Graaf SFJ7，Meyer MR1,8，Maurer HH8，Meier K1， 2，Weiss J1,2，Bruckner T9，Alexandrov A10，Urban S2,11，Mikus G1,2，Haefeli WE1,2。
作者信息

1海德堡大学医院临床药理学和药物流行病学系，Im Neuenheimer Feld 410,69120，Heidelberg，Germany。
2德国感染研究中心（DZIF），海德堡合作伙伴网站，Im Neuenheimer Feld 324,69120，德国海德堡。
3 Dr. Margarete Fischer-Bosch泰宾恩大学临床药理学研究所，Auerbachstraße112，70376，德国斯图加特。
4德国感染研究中心（DZIF），Tübingen合作伙伴网站，E.-Aulhorn-Str。 6，72076，Tübingen，德国。
5德国Tübingen大学医院Tübingen临床药理学系，Auf der Morgenstelle 8，72076。
6Tübingen大学药学和生物化学系，Auf der Morgenstelle 8，72076，Tübingen，德国。
7 Tytgat肝脏和肠道研究所，胃肠病学与肝病学系，学术医学中心，Meibergdreef 69-71,150，BK，荷兰阿姆斯特丹。
8实验和临床毒理学，萨尔州大学，Kirrberger Str。 - Geb. 46，66421，Homburg，Germany。
9海德堡大学医院医学生物统计学和医学信息研究所，Im Neuenheimer Feld 305,69120，德国海德堡。
10 Myr GmbH，Weinbergsweg 66,61348，Bad Homburg，Germany。
11 Department of Infectious Diseases，Molecular Virology，Heidelberg University Hospital，Im Neuenheimer Feld 345,69120，Heidelberg，Germany。

抽象

Myrcludex B作为阻断牛磺胆酸共转运多肽（SLC10A1）的乙型肝炎和D型病毒进入抑制剂。我们研究了myrcludex B对细胞色素P450（CYP）3A的血浆胆汁酸处置，替诺福韦药代动力学和肇事者特征的影响。 12名健康志愿者口服300mg替诺福韦地索普定富马酸，10 mg皮下注射Myrcludex B.Myrcludex B增加总血浆胆汁酸暴露18.2倍，无胆汁淤积症状。共轭胆汁酸的升高高达123倍（牛磺胆酸）。替莫福韦联合米非司酮B显示替诺福韦药代动力学无相关变化。联合治疗期间CYP3A活性略有下降29％。 Myrcludex B引起血浆胆汁酸浓度无症状但明显升高，对替诺福韦药代动力学没有相关影响。 CYP3A活性的变化可能是由于胆汁酸信号传导的改变。升高的胆汁酸的长期影响将需要评估。本文受版权保护。版权所有。

©2017 American Society for Clinical Pharmacology and Therapeutics。
关键词：

细胞色素P450 3A4;药物相互作用;乙型肝炎丙型肝炎咪达唑仑清除药代动力学;牛磺胆酸共转运多肽（SLC10A1）

结论：
    28543042
DOI：
    10.1002 / cpt.744