Drug hepatocyte clearance

Transporter and drug development

  • Clin Pharmacol Ther. 2018;104:793-796. Transporters in drug development: scientific and regulatory considerations. Zhang L, Huang SM, Reynolds K, Madabushi R, Zineh I. PubMed
  • J Pharm Pharm Sci. 2018;21:481-495. Non-alcoholic Steatohepatitis (NASH) drug discovery - Building a consensus on ADME screening tools and clinical pharmacology strategies to aid candidate development. Dash RP, Babu RJ, Srinivas NR. PubMed

Transporter regulation

  • Gastroenterology. 2018;155:1578-1592. Solute Carrier Organic Anion Transporter family member 3A1 is a bile acid efflux transporter in cholestasis. Pan Q, Zhang X, Zhang L, Cheng Y, Zhao N, Li F, Zhou X, Chen S, Li J, Xu S, Huang D, Chen Y, Li L, Wang H, Chen W, Cai SY, Boyer JL, Chai J. The authors propose a model for hepatic OATP3A1 expression regulation in human cholestasis. Increased plasma FGF19 activates ERK and NF-kB signaling, which leads to the increased expression of the transcription factors SP1 and NF-kB p65 and their binding activities to the SLCO3A1 promoter. The increased OATP3A1 expression eliminates conjugated bile acids in cholestatic hepatocytes. On the other hand, FGF19 also represses bile acid synthesis through the ERK/NF-kB–SHP/CYP7A1 pathway. This dual safety mechanism would be effective to eliminate bile acids in cholestatic hepatocytes and thereby reduce liver injury. PubMed
  • Drug Metab Dispos. 2018;46:1478-1486. Gene-by-environment interaction of Bcrp-/- and methionine- and choline-deficient diet-induced Nonalcoholic Steatohepatitis alters SN-38 disposition. Toth EL, Li H, Dzierlenga AL, Clarke JD, Vildhede A, Goedken M, Cherrington NJ. PubMed
  • Drug Metab Dispos. 2018;46:1886-1899. Polymorphisms of the multidrug pump ABCG2: A systematic review of their effect on protein expression, function, and drug pharmacokinetics. Heyes N, Kapoor P, Kerr ID. PubMed
  • Pharmaceutics. 2018;10 pii: E246. mRNA expression and activity of Nucleoside Transporters in human hepatoma HepaRG Cells. Mayati A, Moreau A, Jouan E, Febvre-James M, Denizot C, Parmentier Y, Fardel O. PubMed
  • Clin Pharmacol Ther. 2018;104:1182-1190. Cytochrome P450 3A induction predicts P-glycoprotein induction; Part 1: Establishing induction relationships using ascending dose Rifampin. Lutz JD, Kirby BJ, Wang L, Song Q, Ling J, Massetto B, Worth A, Kearney BP, Mathias A. PubMed
  • Clin Pharmacol Ther. 2018;104:1191-1198. Cytochrome P450 3A induction predicts P-glycoprotein induction; Part 2: Prediction of decreased substrate exposure after Rifabutin or Carbamazepine. Lutz JD, Kirby BJ, Wang L, Song Q, Ling J, Massetto B, Worth A, Kearney BP, Mathias A. PubMed
  • Clin Pharmacol Ther. 2018;104:1249-1259. Drinking ethanol has few acute effects on CYP2C9, CYP2C19, NAT2, and P-Glycoprotein activities but somewhat inhibits CYP1A2, CYP2D6, and intestinal CYP3A: So what? Gazzaz M, Kinzig M, Schaeffeler E, Jübner M, Hsin CH, Li X, Taubert M, Trueck C, Iltgen-Breburda J, Kraus D Queckenberg C, Stoffel M, Schwab M, Sörgel F, Fuhr U. PubMed
  • J Pharm Pharm Sci. 2018;21:325s-334s. STAT3 is involved in IL-6-mediated downregulation of hepatic transporters in mice. Abualsunun WA, Piquette-Miller M. PubMed
  • Mol Pharmacol. 2018;94:1412-1420. The 5'-AMP-activated protein kinase regulates the function and expression of human Organic Anion Transporting Polypeptide 1A2. Lu X, Chan T, Cheng Z, Shams T, Zhu L, Murray M, Zhou F. PubMed

Physiologically Based Pharmacokinetic Modeling

  • Clin Pharmacol Ther. 2018;104:1219-1228. Physiologically Based Pharmacokinetic Modeling to identify physiological and molecular characteristics driving variability in drug exposure. Rowland A, van Dyk M, Hopkins AM, Mounzer R, Polasek TM, Rostami-Hodjegan A, Sorich MJ. PubMed
  • Eur J Pharm Sci. 2018;125:181-192. Strategies to improve the prediction accuracy of hepatic intrinsic clearance of three antidiabetic drugs: Application of the extended clearance concept and consideration of the effect of albumin on CYP2C metabolism and OATP1B-mediated hepatic uptake. Fujino R, Hashizume K, Aoyama S, Maeda K, Ito K, Toshimoto K, Lee W, Ninomiya SI, Sugiyama Y. PubMed

Drug hepatoprotection

  • Front Pharmacol. 2018;9:1115. Baicalein enhances the oral bioavailability and hepatoprotective effects of Silybin through the inhibition of efflux transporters BCRP and MRP2. Xu P, Zhou H, Li YZ, Yuan ZW, Liu CX, Liu L, Xie Y. PubMed

Quality control of subcellular fractionation procedures

  • Anal Chem. 2018;90:11873-11882. Targeted LC-MS/MS proteomics-based strategy to characterize in vitro models used in drug metabolism and transport studies. Xu M Saxena N, Vrana M, Zhang H, Kumar V, Billington S, Khojasteh C, Heyward S, Unadkat JD, Prasad B. PubMed

Drugs and bile flow

  • Eur J Pharmacol. 2018;838:91-106. Evidence that decreased expression of sinusoidal bile acid transporters accounts for the inhibition by rapamycin of bile flow recovery following liver ischemia. Afroz F, Jonkman E, Hua J, Kist A, Zhou Y, Sokoya EM, Padbury R, Nieuwenhuijs V, Barritt G. PubMed