Prediction of the Clinical Risk of Drug-Induced Cholestatic Liver Injury Using an In Vitro Sandwich Cultured Hepatocyte Assay

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Takeshi SusukidaKousei Ito

Abstract

Drug-induced liver injury (DILI) is of concern to the pharmaceutical industry, and reliable preclinical screens are required. Previously, we established an in vitro bile acid-dependent hepatotoxicity assay that mimics cholestatic DILI in vivo. Here, we confirmed that this assay can predict cholestatic DILI in clinical situations by comparing in vitro cytotoxicity data with in vivo risk. For 38 drugs, the frequencies of abnormal increases in serum alkaline phosphatase (ALP), transaminases, gamma glutamyltranspeptidase (γGT), and bilirubin were collected from interview forms. Drugs with frequencies of serum marker increases higher than 1% were classified as high DILI risk compounds. In vitro cytotoxicity was assessed by monitoring lactate dehydrogenase release from rat and human sandwich-cultured hepatocytes (SCRHs and SCHHs) incubated with the test drugs (50 μM) for 24 hours in the absence or presence of a bile acids mixture. Receiver operating characteristic analyses gave optimal cutoff toxicity values of 19.5% and 9.2% for ALP and transaminases in SCRHs, respectively. Using this cutoff, high- and low-risk drugs were separated with 65.4-78.6% sensitivity and 66.7-79.2% specificity. Good separation was also achieved using SCHHs....Continue Reading

References

Feb 5, 2002·Annual Review of Physiology·Peter J Meier, B Stieger
Feb 4, 2003·Toxicological Sciences : an Official Journal of the Society of Toxicology·Irene D RománRoger Coleman
Dec 3, 2003·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Renxue WangVictor Ling
Jan 18, 2006·Toxicological Sciences : an Official Journal of the Society of Toxicology·Seva E KostrubskyAbdul E Mutlib
May 14, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Ken GrimeRobert J Riley
Aug 2, 2008·Nature Reviews. Drug Discovery·Charles ThomasKristina Schoonjans
Aug 4, 2009·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Renxue WangVictor Ling
Oct 13, 2009·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Max SchererGerhard Liebisch
Sep 11, 2010·Toxicological Sciences : an Official Journal of the Society of Toxicology·Ryan E MorganHisham K Hamadeh
Oct 4, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Sarah DawsonJ Gerald Kenna
Nov 24, 2011·Biochemical and Biophysical Research Communications·Eiichiro OgimuraToshiharu Horie
Feb 22, 2012·Toxicology and Applied Pharmacology·Tracy L MarionKim L R Brouwer
Oct 11, 2012·World Journal of Gastroenterology : WJG·Benjamin L Woolbright, Hartmut Jaeschke
Feb 8, 2013·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Neil Kaplowitz
Aug 21, 2013·Toxicological Sciences : an Official Journal of the Society of Toxicology·Ryan E MorganHisham K Hamadeh
Sep 10, 2013·Toxicological Sciences : an Official Journal of the Society of Toxicology·Jenny M PedersenPer Artursson
May 7, 2014·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Michael D AleoYvonne Will
May 7, 2014·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Kyunghee Yang, Kim L R Brouwer
Jun 1, 2014·Seminars in Liver Disease·Mark I Avigan
Jun 18, 2014·The American Journal of Gastroenterology·Naga P ChalasaniUNKNOWN Practice Parameters Committee of the American College of Gastroenterology
Jun 10, 2015·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Takeshi SusukidaKousei Ito
Jun 24, 2015·Drug Metabolism and Pharmacokinetics·Nontaya NakkamWichittra Tassaneeyakul

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Citations

Mar 10, 2016·Journal of Pharmaceutical Sciences·Takeshi SusukidaKousei Ito
Apr 21, 2016·Toxicology and Applied Pharmacology·Cong LiuKousei Ito
Jun 4, 2016·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Akinori TakemuraKousei Ito
Nov 20, 2016·Clinical Pharmacology and Therapeutics·M Mosedale, P B Watkins
May 23, 2018·Journal of Applied Toxicology : JAT·Rhishikesh ThakareYazen Alnouti
Jun 12, 2018·Expert Opinion on Drug Metabolism & Toxicology·Petar D PetrovRamiro Jover
Sep 1, 2018·European Journal of Drug Metabolism and Pharmacokinetics·Olivier FardelYannick Parmentier
Nov 3, 2020·Nihon yakurigaku zasshi. Folia pharmacologica Japonica·Akinori Takemura, Kousei Ito
Feb 11, 2020·Journal of Medicinal Chemistry·Merrie Mosedale, Paul B Watkins

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