Intracellular concentrations

  • Drug Metab Dispos. 2017;45:1292-1303. Progressive and preferential cellular accumulation of hydrophobic bile acids induced by cholestatic drugs is associated with inhibition of their amidation and sulfation. Sharanek A, Burban A, Humbert L, Guguen-Guillouzo C, Rainteau D, Guillouzo A. Drug-induced intrahepatic cholestasis is characterised by cellular accumulation of bile acids, whose mechanisms remain poorly understood. The present study analyses early and progressive alterations of bile acid profiles induced by cyclosporine A, chlorpromazine, troglitazone, tolcapone, trovafloxacin, and tacrolimus after 4-hour, 24-hour, and 6-day treatments of differentiated HepaRG cells. PubMed

Expression of transporters

  • Drug Metab Dispos. 2018;46:189-196. Transporter expression in noncancerous and cancerous liver tissue from donors with hepatocellular carcinoma and chronic hepatitis C infection quantified by LC-MS/MS proteomics. Billington S, Ray AS, Salphati L, Xiao G, Chu X, Humphreys WG, Liao M, Lee CA, Mathias A, Hop CECA, Rowbottom C, Evers R, Lai Y, Kelly EJ, Prasad B, Unadkat JD. In this publication, protein expression of major hepatobiliary drug transporters (NTCP, OATPs, OCT1, BSEP, BCRP, MATE1, MRPs, and P-gp) in cancerous and adjacent noncancerous liver tissues obtained from patients with chronic hepatitis C with hepatocellular carcinoma are quantified by LC-MS/MS proteomics. PubMed

  • Drug Metab Dispos. 2018;46:66-74. Successful prediction of in vivo hepatobiliary clearances and hepatic concentrations of Rosuvastatin using sandwich-cultured rat hepatocytes, transporter-expressing cell lines, and quantitative proteomics. Ishida K, Ullah M, Tóth B, Juhasz V, Unadkat JD. Protein expression of Oatps in sandwich-cultured rat hepatocytes and Oatp-expressing cells is quantified by liquid chromatography tandem mass spectrometry. PubMed

Transport of compounds

  • Pharm Res. 2017; 34:2336-2348. Role of the OATP transporter family and a Benzbromarone-sensitive efflux transporter in the hepatocellular disposition of Vincristine. Nicolaï J, Thevelin L, Bing Q, Stieger B, Chanteux H, Augustijns P, Annaert P. PubMed
  • Drug Metab Dispos. 2018;46:33-40. Organic Cation Transporter 1 is responsible for hepatocellular uptake of the Tyrosine Kinase Inhibitor Pazopanib. Ellawatty WEA, Masuo Y, Fujita KI, Yamazaki E, Ishida H, Arakawa H, Nakamichi N, Abdelwahed R, Sasaki Y, Kato Y. PubMed
  • Clin Pharmacol Ther. 2017;102:726-730. Kinase inhibitors: the reality behind the success. Jeon JY, Sparreboom A, Baker SD. Tremendous progress has been made by utilizing kinase inhibitors in oncology, and these agents continue to pave the way into other areas of medicine. There are, however, many challenges to the application of kinase inhibitors due to inherent shortcomings of the drugs and lack of comprehensive understanding of tumour and disease biology. The future fate of kinase inhibitors, however, is bright, as evidenced from ongoing efforts to increase their efficacy while remediating their weaknesses in order to provide the best quality of care to patients. PubMed

Bile acid transport

  • Clin Pharmacol Ther. 2018;103: 341-348. The NTCP - inhibitor myrcludex B: Effects on bile acid disposition and tenofovir pharmacokinetics. Blank A, Eidam A, Haag M, Hohmann N, Burhenne J, Schwab M, van de Graaf SFJ, Meyer MR, Maurer HH, Meier K Weiss J, Bruckner T, Alexandrov A, Urban S, Mikus G, Haefeli WE. Myrcludex B acts as a hepatitis B and D virus entry inhibitor blocking the sodium taurocholate cotransporting polypeptide (SLC10A1). The study investigates the effects of myrcludex B on plasma bile acid disposition, tenofovir pharmacokinetics, and perpetrator characteristics on cytochrome P450 (CYP) 3A. PubMed
  • Hepatology. 2017;66:1631-1643. Hepatic uptake of conjugated bile acids is mediated by both sodium taurocholate cotransporting polypeptide and organic anion transporting polypeptides and modulated by intestinal sensing of plasma bile acid levels in mice. Slijepcevic D, Roscam Abbing RLP, Katafuchi T, Blank A, Donkers JM, van Hoppe S, de Waart DR, Tolenaars D, van der Meer JHM, Wildenberg M, Beuers U, Oude Elferink RPJ, Schinkel AH, van de Graaf SFJ. NTCP and OATPs contribute to hepatic uptake of conjugated bile acids in mice, whereas the predominant uptake in humans is NTCP-mediated. Enterocytes sense highly elevated levels of (conjugated) bile acids in the systemic circulation to induce FGF15/19, which modulates hepatic bile acid synthesis and uptake. PubMed
  • J Hepatol. 2017;67:1253-1264. Sequencing of FIC1, BSEP and MDR3 in a large cohort of patients with cholestasis revealed a high number of different genetic variants. Dröge C, Bonus M, Baumann U, Klindt C, Lainka E, Kathemann S, Brinkert F, Grabhorn E, Pfister ED, Wenning D, Fichtner A, Gotthardt DN, Weiss KH, McKiernan P, Puri RD, Verma IC9 Kluge S, Gohlke H, Schmitt L, Kubitz R, Häussinger D, Keitel V. PubMed

Liver imaging

  • Clin Pharmacol Ther. 2017, 102, 841-848 Genetic polymorphisms in Organic Cation Transporter 1 attenuates hepatic Metformin exposure in humans. Sundelin EIO, Gormsen LC, Jensen JB, Vendelbo MH, Jakobsen S, Munk OL, Christensen M, Brøsen K, Frøkiaer J, Jessen N. This study examines if common polymorphisms in SLC22A1, encoding the transporter protein OCT1, affect the hepatic distribution of metformin in humans. PubMed
  • J Pharm Sci. 2017;106:2335-2344. Imaging probes and modalities for the study of Solute Carrier O (SLCO)-transport function in vivo. Marie S, Cisternino S, Buvat I, Declèves X, Tournier N. The review reports and compares imaging probes that have been proposed to study SLCO-transport function, in terms of in vitro specificity, in vivo behavior, and clinical validation. PubMed
  • Hepatology. 2018;67:401-421. Imaging for the diagnosis of hepatocellular carcinoma: A systematic review and meta-analysis. Roberts LR, Sirlin CB, Zaiem F, Almasri J, Prokop LJ, Heimbach JK, Murad MH, Mohammed K. PubMed

Drug-drug interactions and endogenous probes

  • J Pharm Sci. 2017;106:2357-2367. Identification of endogenous biomarkers to predict the propensity of drug candidates to cause hepatic or renal transporter-mediated drug-drug interactions. Chu X, Chan GH, Evers R. Several endogenous compounds have been identified as substrates of drug transporters. Determining the impact of perpetrator drugs on the plasma or urinary exposure of these potential endogenous biomarkers in humans is being explored as an alternative approach to assess the DDI liability of drug candidates, especially in early drug development. PubMed