Drug–Drug Interaction Potential of the HBV and HDV Entry Inhibitor Myrcludex B Assessed in vitro

World Health Organization. Guidelines for the prevention, care, and treatment of persons with chronic hepatitis B infection. (Updated March 2015. Accessed 15 May 2017.) Available from http://www.who.int/hiv/pub/hepatitis/hepatitis-b-guidelines/en/.

World Health Organization. Fact sheet hepatitis D. (Updated July 2016. Accessed 24 January 2017.) Available from http://www.who.int/mediacentre/factsheets/hepatitis-d/en/.

Lok A.S. , McMahon B.J. , Brown R.S. Jr. Antiviral therapy for chronic hepatitis B viral infection in adults: a systematic review and meta-analysis. Hepatology 2016; 63: 284–306.

Gunsar F. Treatment of delta hepatitis. Expert Rev Anti Infect Ther 2013; 11: 489–498.

Koh C. , Canini L. , Dahari H. Oral prenylation inhibition with lonafarnib in chronic hepatitis D infection: a proof-of-concept randomised, double-blind, placebo-controlled Phase 2A trial. Lancet Infect Dis 2015; 15: 1167–1174.

Vaillant A. Nucleic acid polymers: broad spectrum antiviral activity, antiviral mechanisms and optimization for the treatment of hepatitis B and hepatitis D infection. Antiviral Res 2016; 133: 32–40.

Urban S. , Bartenschlager R. , Kubitz R. , Zoulim F. Strategies to inhibit entry of HBV and HDV into hepatocytes. Gastroenterology 2014; 147: 48–64.

Lempp F.A. , Urban S. Inhibitors of hepatitis B virus attachment and entry. Intervirology 2014; 57: 151–157.

Lütgehetmann M. , Mancke L.V. , Volz T. Humanized chimeric uPA mouse model for the study of hepatitis B and D virus interactions and preclinical drug evaluation. Hepatology 2012; 55: 685–694.

Petersen J. , Dandri M. , Mier W. Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein. Nat Biotechnol 2008; 26: 335–341.

Volz T. , Allweiss L. , Barek M.B. The entry inhibitor myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus. J Hepatol 2013; 58: 861–867.

Ni Y. , Lempp F.A. , Mehrle S. Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for species-specific entry into hepatocytes. Gastroenterology 2014; 146: 1070–1083.

Blank A. , Markert C. , Hohmann N. First-in-human application of the first-in-class hepatitis B and hepatitis D virus entry inhibitor myrcludex B. J Hepatol 2016; 65: 483–489.

Bogomolov P. , Alexandrov A. , Voronkova N. Treatment of chronic hepatitis D with the entry inhibitor myrcludex B - first results of a Phase Ib/IIa study. J Hepatol 2016; 65: 490–498.

Schinkel A.H. , Wagenaar E. , van Deemter L. , Mol C.A. , Borst P. Absence of the mdr1a P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin and cyclosporin A. J Clin Invest 1995; 96: 1698–1705.

Weiss J. , Dormann S.M. , Martin-Facklam M. , Kerpen C.J. , Ketabi-Kiyanvash N. , Haefeli W.E. Inhibition of P-glycoprotein by newer antidepressants. J Pharmacol Exp Ther 2003; 305: 197–204.

Pavek P. , Merino G. , Wagenaar E. Human breast cancer resistance protein: interactions with steroid drugs, hormones, the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine, and transport of cimetidine. J Pharmacol Exp Ther 2005; 312: 144–152.

Weiss J. , Rose J. , Storch C.H. Modulation of human BCRP (ABCG2) activity by anti-HIV drugs. J Antimicrob Chemother 2007; 59: 238–245.

König J. , Cui Y. , Nies A.T. , Keppler D. Localization and genomic organization of a new hepatocellular organic anion transporting polypeptide. J Biol Chem 2000; 275: 23161–23168.

König J. , Cui Y. , Nies A.T. , Keppler D. A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane. Am J Physiol Gastrointest Liver Physiol 2000; 278: G156–G164.

Peters T. , Lindenmaier H. , Haefeli W.E. , Weiss J. Interaction of the mitotic kinesin Eg5 inhibitor monastrol with P-glycoprotein. Naunyn Schmiedebergs Arch Pharmacol 2006; 372: 291–299.

Weiss J. , Herzog M. , Haefeli W.E. Differential modulation of the expression of important drug metabolising enzymes and transporters by endothelin-1 receptor antagonists ambrisentan and bosentan in vitro. Eur J Pharmacol 2011; 660: 298–304.

Weiss J. , Theile D. , Spalwisz A. , Burhenne J. , Riedel K.D. , Haefeli W.E. Influence of sildenafil and tadalafil on the enzyme- and transporter-inducing effects of bosentan and ambrisentan in LS180 cells. Biochem Pharmacol 2013; 85: 265–273.

Harmsen S. , Koster A.S. , Beijnen J.H. , Schellens J.H. , Meijerman I. Comparison of two immortalized human cell lines to study nuclear receptor-mediated CYP3A4 induction. Drug Metab Dispos 2008; 36: 1166–1171.

Gupta A. , Mugundu G.M. , Desai P.B. , Thummel K.E. , Unadkat J.D. Intestinal human colon adenocarcinoma cell line LS180 is an excellent model to study pregnane X receptor, but not constitutive androstane receptor, mediated CYP3A4 and multidrug resistance transporter 1 induction: studies with anti-human immunodeficiency virus protease inhibitors. Drug Metab Dispos 2008; 36: 1172–1180.

Brandin H. , Viitanen E. , Myrberg O. , Arvidsson A.K. Effects of herbal medicinal products and food supplements on induction of CYP1A2; CYP3A4 and MDR1 in the human colon carcinoma cell line LS180. Phytother Res 2007; 21: 239–244.

Yamasaki D. , Nakamura T. , Okamura N. Effects of acid and lactone forms of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on the induction of MDR1 expression and function in LS180 cells. Eur J Pharm Sci 2009; 37: 126–132.

Li W. , Harper P.A. , Tang B.K. , Okey A.B. Regulation of cytochrome P450 enzymes by aryl hydrocarbon receptor in human cells: CYP1A2 expression in the LS180 colon carcinoma cell line after treatment with 2;3;7;8-tetrachlorodibenzo-p-dioxin or 3-methylcholanthrene. Biochem Pharmacol 1998; 56: 599–612.

Harper P.A. , Prokipcak R.D. , Bush L.E. , Golas C.L. , Okey A.B. Detection and characterization of the Ah receptor for 2;3;7;8-tetrachlorodibenzo-p-dioxin in the human colon adenocarcinoma cell line LS180. Arch Biochem Biophys 1991; 290: 27–36.

Albermann N. , Schmitz-Winnenthal F.H. , Z'graggen K. Expression of the drug transporters MDR1/ABCB1, MRP1/ABCC1, MRP2/ABCC2, BCRP/ABCG2, and PXR in peripheral blood mononuclear cells and their relationship with the expression in intestine and liver. Biochem Pharmacol 2005; 70: 949–958.

Zembruski N.C. , Büchel G. , Jödicke L. , Herzog M. , Haefeli W.E. , Weiss J. Potential of novel antiretrovirals to modulate expression and function of drug transporters in vitro. J Antimicrob Chemother 2011; 66: 802–812.

Vandesompele J. , De Preter K. , Pattyn F . Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 2002; 3: RESEARCH0034.

Okey A.B. , Riddick D.S. , Harper P.A. The Ah receptor: mediator of the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. Toxicol Lett 1994; 70: 1–22.

Geick A. , Eichelbaum M. , Burk O. Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem 2001; 276: 14581–14587.

Kliewer S.A. , Goodwin B. , Willson T.M. The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism. Endocr Rev 2002; 23: 687–702.

Kast H.R. , Goodwin B. , Tarr P.T. Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor. J Biol Chem 2002; 277: 2908–2915.

Ebert B. , Seidel A. , Lampen A. Identification of BCRP as transporter of benzo[a]pyrene conjugates metabolically formed in Caco-2 cells and its induction by Ah-receptor agonists. Carcinogenesis 2005; 26: 1754–1763.

Jigorel E. , Le Vee M. , Boursier-Neyret C. , Parmentier Y. , Fardel O. Differential regulation of sinusoidal and canalicular hepatic drug transporter expression by xenobiotics activating drug-sensing receptors in primary human hepatocytes. Drug Metab Dispos 2006; 34: 1756–1763.

Urquhart B.L. , Tirona R.G. , Kim R.B. Nuclear receptors and the regulation of drug-metabolizing enzymes and drug transporters: implications for interindividual variability in response to drugs. J Clin Pharmacol 2007; 47: 566–578.

Lankisch T.O. , Gillman T.C. , Erichsen T.J. Aryl hydrocarbon receptor-mediated regulation of the human estrogen and bile acid UDPglucuronosyltransferase 1A3 gene. Arch Toxicol 2008; 82: 573–582.

Tolson A.H. , Wang H. Regulation of drug-metabolizing enzymes by xenobiotic receptors: PXR and CAR. Adv Drug Deliv Rev 2010; 62: 1238–1249.

Blank A. , Eidam A. , Haag M. The NTCP-inhibitor myrcludex B: effects on bile acid disposition and tenofovir pharmacokinetics. Clin Pharmacol Ther 2018; 103: 341–348.

Schuetz E.G. , Strom S. , Yasuda K. Disrupted bile acid homeostasis reveals an unexpected interaction among nuclear hormone receptors, transporters, and cytochrome P450. J Biol Chem 2001; 276: 39411–39418.

Iwamoto J. , Saito Y. , Honda A. Bile acid malabsorption deactivates pregnane X receptor in patients with Crohn's disease. Inflamm Bowel Dis 2013; 19: 1278–1284.

Molina D.K. , DiMaio V.J. Normal organ weights in men: part II-the brain, lungs, liver, spleen, and kidneys. Am J Forensic Med Pathol 2012; 33: 368–372.

Dawson P.A. Role of the intestinal bile acid transporters in bile acid and drug disposition. Handb Exp Pharmacol 2011; 201: 169–203.

Slijepcevic D. , Roscam Abbing R.L.P. , Katafuchi T. Hepatic uptake of conjugated bile acids is mediated by both NTCP and OATPs and modulated by intestinal sensing of plasma bile acid levels in mice. Hepatology 2017; doi:10.1002/hep.29251.

Suga T. , Yamaguchi H. , Sato T. , Maekawa M. , Goto J. , Mano N. Preference of conjugated bile acids over unconjugated bile acids as substrates for OATP1B1 and OATP1B3. PLoS One 2017; 12: e0169719.