Utility of in vitro systems and preclinical data for the prediction of human intestinal first-pass metabolism during drug discovery and preclinical development

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Fredrik H KarlssonSheila Annie Peters

Abstract

A growing awareness of the risks associated with extensive intestinal metabolism has triggered an interest in developing robust methods for its quantitative assessment. This study explored the utility of intestinal S9 fractions, human liver microsomes, and recombinant cytochromes P450 to quantify CYP3A-mediated intestinal extraction in humans for a selection of marketed drugs that are predominantly metabolized by CYP3A4. A simple competing rates model is used to estimate the fraction of drug escaping gut wall metabolism (fg) from in vitro intrinsic clearance in humans. The fg values extrapolated from the three in vitro systems used in this study, together with literature-derived fg from human intestinal microsomes, were validated against fg extracted from human in vivo pharmacokinetic (PK) profiles using a generic whole-body physiologically-based pharmacokinetic (PBPK) model. The utility of the rat as a model for human CYP3A-mediated intestinal metabolism was also evaluated. Human fg from PBPK compares well with that from the grapefruit juice method, justifying its use for the evaluation of human in vitro systems. Predictive performance of all human in vitro systems was comparable [root mean square error (RMSE) = 0.22-0.27; n =...Continue Reading

References

Sep 1, 1991·Digestive Diseases and Sciences·R T YavorskiP W Blue
Feb 1, 1990·Annals of Medicine·B R Goldin
Jun 1, 1989·European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology·B Ljungberg, I Nilsson-Ehle
Mar 31, 1986·The American Journal of Medicine·R E GammansJ A LaBudde
Apr 1, 1973·Journal of Pharmacokinetics and Biopharmaceutics·M RowlandG G Graham
May 13, 1998·British Journal of Clinical Pharmacology·H H KupferschmidtS Krähenbühl
Oct 16, 1999·Journal of Controlled Release : Official Journal of the Controlled Release Society·L Z BenetV J Wacher
Aug 8, 2002·Journal of Pharmacological and Toxicological Methods·H ZahirA J McLachlan
Nov 16, 2002·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Rupert P AustinRobert J Riley
Nov 20, 2003·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Laurence S Kaminsky, Qing-Yu Zhang
May 26, 2004·International Journal of Pharmaceutics·L Z BenetC Y Wu
Apr 2, 2005·Biological & Pharmaceutical Bulletin·Young-Joo LeeChang-Koo Shim
Apr 29, 2005·Journal of Pharmaceutical Sciences·Trudy RodgersMalcolm Rowland
Jun 28, 2005·Toxicology and Applied Pharmacology·P I MackenzieD A Gardner-Stephen
Feb 7, 2006·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Hiroshi SaitohBruce J Aungst
Feb 10, 2006·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Mary F PaineDarryl C Zeldin
Aug 18, 2006·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Esther G van de KerkhofGeny M M Groothuis
Feb 3, 2007·Expert Opinion on Drug Metabolism & Toxicology·Joseph K Ritter
Sep 14, 2007·Journal of Pharmaceutical Sciences·Hiroshi Komura, Masahiro Iwaki
Nov 6, 2007·Current Drug Metabolism·Esther G van de KerkhofGeny M M Groothuis
Nov 6, 2007·Current Drug Metabolism·Jiansong YangAmin Rostami-Hodjegan
Dec 1, 2007·Nucleic Acids Research·David S WishartMurtaza Hassanali
Mar 12, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Doreen MitschkeUrsula Moenning
Apr 23, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·R Scott ObachNigel J Waters
Jul 16, 2008·Expert Opinion on Drug Metabolism & Toxicology·Aleksandra GaletinJ Brian Houston
Feb 21, 2009·Journal of Pharmaceutical Sciences·Masayuki TakahashiShinji Yamashita
May 2, 2009·The Journal of Pharmacy and Pharmacology·Kirstin Thelen, Jennifer B Dressman
Nov 17, 2009·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Takafumi AkabaneToshio Teramura
Apr 1, 2010·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Keitaro KadonoToshio Teramura
Apr 7, 2010·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Michael GertzAleksandra Galetin
Jun 3, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Michael GertzAleksandra Galetin

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Citations

Nov 6, 2014·Archives of Toxicology·Ahmed Ghallab, H M Bolt
Dec 25, 2015·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Xin YangLi Di
Jan 2, 2016·Pharmacological Reviews·Janne T BackmanPertti J Neuvonen
Jan 29, 2014·British Journal of Pharmacology·Darren Michael Moss, Marco Siccardi
Apr 16, 2016·Future Medicinal Chemistry·Lixia Gao, Yong Teng
Jul 17, 2015·Oxidative Medicine and Cellular Longevity·Loai Basheer, Zohar Kerem
May 18, 2005·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Rhonda M BrandSusan L Cuppett
Oct 7, 2016·Acta Pharmaceutica Sinica. B·Fang XieQing-Yu Zhang
Feb 6, 2017·Biopharmaceutics & Drug Disposition·Estelle YauSheila Annie Peters
Apr 18, 2017·Journal of Pharmaceutical Sciences·Jingjing YuIsabelle Ragueneau-Majlessi
Sep 2, 2018·British Journal of Clinical Pharmacology·Niladri ChattopadhyayMarcus-Hillert Schultze-Mosgau
Oct 17, 2013·Drug Metabolism and Disposition : the Biological Fate of Chemicals·J Brian Houston
Oct 18, 2014·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Yuan ChenCornelis E C A Hop
Mar 4, 2020·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Keiichi MoritaKiyomi Ito
Jun 23, 2015·Journal of Cellular Physiology·Valeria De ArcangelisLucia Monaco
Aug 31, 2020·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Mari DaviesNenad Manevski

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