2017 SEPTEMBER

NEW PUBLICATIONS FROM NETWORK MEMBERS 

Basic pharmacology

  • Clin Transl Sci. 2017;10:271-279. Influence of OATP1B1 function on the disposition of Sorafenib-β-D-glucuronide. Bins S, van Doorn L, Phelps MA, Gibson AA, Hu S, Li L, Vasilyeva A, Du G, Hamberg P4, Eskens F, de Bruijn P, Sparreboom A, Mathijssen R, Baker SD. PubMed The study emphasises the need to consider hepatic handling of xenobiotic glucuronides in the design of drug-drug interaction studies of agents that undergo extensive phase II conjugation.
  • Int J Mol Sci. 2017;18: E764. Protein Kinases C-mediated regulations of drug transporter activity, localization and expression. Mayati A, Moreau A, Le Vée M, Stieger B, Denizot C, Parmentier Y, Fardel O. PubMed In the present review, the implications of protein kinases C (PKCs) in transporter regulations are summarized and discussed.
  • Eur J Pharm Sci. 2017;103:52-59. Identification of novel MRP3 inhibitors based on computational models and validation using an in vitro membrane vesicle assay. Ali I, Welch MA, Lu Y, Swaan PW, Brouwer KLR. PubMed Multidrug resistance-associated protein 3 (MRP3) may prevent the accumulation of anionic substrates (bile acids) in hepatocytes. Inhibition of MRP3 may then disrupt bile acid homeostasis and induce drug-induced liver injury (DILI). Identifying potential MRP3 inhibitors may mitigate the occurrence of DILI. Novel MRP3 inhibitors are identified by virtual screening using the selected Bayesian model, and MRP3 inhibition is confirmed by an in vitro transporter inhibition assay. Information generated using this modelling approach may be valuable in predicting the potential for DILI and/or MRP3-mediated drug-drug interactions.
  • Drug Metab Dispos. 2017;45:523-531. Assessing the risk of drug-induced cholestasis using unbound intrahepatic concentrations. Riede J, Poller B, Huwyler J, Camenisch G. PubMed

Liver (and brain) imaging

  • J Hepatol. 2017; 67:321–327. Hepatobiliary transport kinetics of the conjugated bile acid tracer 11C-CSar quantified in healthy humans and patients by positron emission tomography. Ørntoft NW, Munk OL, Frisch K, Ott P, Keiding S, Sørensen M. PubMed Positron emission tomography (PET) using the radiolabelled bile acid (11C-CSar) enables the transport quantification of bile acids from blood to bile in man. Cholestasis reduces uptake and secretion of the bile acid and increases its backflux to blood. These findings improve our understanding of cholestatic liver diseases and may support therapeutic decisions.
  • Nucl Med Biol. 2017;52:7-15. [11C]Erlotinib PET cannot detect acquired erlotinib resistance in NSCLC tumor xenografts in mice. Traxl A, Beikbaghban T, Wanek T, Kryeziu K, Pirker C, Mairinger S, Stanek J, Filip T, Sauberer M, Kuntner C, Berger W, Langer O. PubMed
  • Br J Clin Pharmacol. 2017;83:1991-1999. Effect of P-glycoprotein inhibition at the Blood-Brain Barrier on brain distribution of (R)-[11 C]verapamil in elderly vs. young subjects. Bauer M, Wulkersdorfer B, Karch R, Philippe C, Jäger W, Stanek J, Wadsak W, Hacker M, Zeitlinger M, Langer O. PubMed
  • J Pharm Sci. 2017;106:2780-2786. A prediction method for P-glycoprotein-mediated drug-drug interactions at the human Blood-Brain Barrier from blood concentration-time profiles, validated with PET data. Matsuda A, Karch R, Bauer M, Traxl A, Zeitlinger M, Langer O. PubMed
  • Drug Metab Dispos. 2017;45:1093-1100. Hepatocyte-specific deletion of EGFR in mice eeduces hepatic Abcg2 transport activity measured by [11C]erlotinib and Positron Emission Tomography. Traxl A, Komposch K, Glitzner E, Wanek T, Mairinger S, Langer O, Sibilia M. PubMed The study shows that EGFR deletion in hepatocytes leads to a reduction in Abcg2-mediated hepatobiliary clearance of a probe substrate accompanied by a shift to renal excretion of the drug. This result raises the possibility that EGFR-inhibiting drugs may mediate ABCG2-related DDIs

NEW PUBLICATIONS FROM OTHER RESEARCH GROUPS

Drug-induced liver injury

  • J Hepatol. 2017;67:84-91. Reversibility of chemotherapy-related liver injury. Vigano L, De Rosa G, Toso C, Andres A, Ferrero A, Roth A, Sperti E, Majno P, Rubbia-Brandt L. PubMed Patients with colorectal liver metastases often receive chemotherapy before liver resection, but this chemotherapy causes liver injuries, increasing operative risks and reducing tolerance to further chemotherapy. The authors analyse the reversibility of liver injuries after the chemotherapy interruption and show that liver injuries persist for a long time after chemotherapy. Sinusoidal dilatation and nodular regenerative hyperplasia regress only nine months after the end of chemotherapy, whereas steatosis and steatohepatitis persist even after this long interval.
  • Hepatology. 2017;66:646-654.  Drug rechallenge following drug-induced liver injury. Hunt CM, Papay JI, Stanulovic V, Regev A. PubMed For critical medicines, drug rechallenge may be appropriate when 1) no safer alternatives are available; 2) the objective benefit exceeds the risk; and 3) patients are fully informed and consent, can adhere to follow-up, and alert providers to hepatitis symptoms. To better understand rechallenge outcomes and identify key risk factors for positive rechallenge, additional data are needed from controlled clinical trials, prospective registries, and large health care databases.
  • Clin Pharmacol Ther. 2017;102:391-394. A call for a consortium for optimal management of drug-drug interactions in patient care. Burger DM, Smolders EJ, Schapiro J, Drenth J, Back DJ. PubMed During clinical development of medicines, manufacturers are obliged to assess the risk of drug-drug interactions (DDIs) with their new drug. There is no doubt that product labels of drugs that are nowadays introduced to the market contain much more information on DDIs than in the past. Indeed, the drug label is often the first source for DDIs available to physicians and pharmacists. But how informative are the data presented in the drug labels? A call for a consortium for optimal management of drug-drug interactions in patient care is needed.

Myotoxicity of statins and transporters

  • Pharmacol Ther. 2017;175:1-16. Myotoxicity of statins: Mechanism of action. du Souich P, Roederer G, Dufour R. PubMed High concentrations of statins in the myocyte may occur whenever the activity of 1) liver influx membrane transporters (OATP1B1), 2) drug metabolizing enzymes; and 3) liver and muscular efflux transporters (MDR1 and BCRP), is reduced.

Cupper transporter

  • Am J Physiol Gastrointest Liver Physiol. 2017;313:G39-G49. Targeted inactivation of copper transporter Atp7b in hepatocytes causes liver steatosis and obesity in mice. Muchenditsi A, Yang H, Hamilton JP, Koganti L, Housseau F, Aronov L, Fan H, Pierson H, Bhattacharjee A, Murphy R, Sears C, Potter J, Wooton-Kee CR, Lutsenko S. PubMed

Basic pharmacology

  • J Pharm Sci. 2017;106:2515-2523. Organic Anion-Transporting Polypeptide and efflux transporter-mediated hepatic uptake and biliary excretion of Cilostazol and its metabolites in rats and humans. Wang C, Huo X, Wang C, Meng Q, Liu Z, Sun P, Cang J, Sun H, Liu K. PubMed
  • Drug Metab Dispos. 2017;45:246-259. Specific inhibition of the distribution of Lobeglitazone to the liver by Atorvastatin in rats: Evidence for a rat Organic Anion Transporting Polypeptide 1B2-mediated interaction in hepatic transport. Yim CS, Jeong YS, Lee SY, Pyeon W, Ryu HM, Lee JH, Lee KR, Maeng HJ, Chung SJ. PubMed
  • Int J Pharm. 2017;520:14-20. Interaction of pharmaceutical excipients with organic cation transporters. Soodvilai S, Soodvilai S, Chatsudthipong V, Ngawhirunpat T, Rojanarata T, Opanasopit P. PubMed
  • Drug Metab Dispos. 2017;45:576-580. Novel method to predict in vivo liver-to-plasma Kpuu for OATP substrates using suspension hepatocytes. Riccardi K, Lin J, Li Z, Niosi M, Ryu S, Hua W, Atkinson K, Kosa RE, Litchfield J, Di L. PubMed

Liver imaging

  • Bioorg Med Chem. 2017;25:963-976.  Design, synthesis, in vitro characterization and preliminary imaging studies on fluorinated bile acid derivatives as PET tracers to study hepatic transporters. Testa A, Dall'Angelo S, Mingarelli M, Augello A, Schweiger L, Welch A, Elmore CS, Sharma P, Zanda M. PubMed

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