Evaluation of the human prediction of clearance from hepatocyte and microsome intrinsic clearance for 52 drug compounds

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
A-K Sohlenius-SternbeckC Petersson

Abstract

We compare three different approaches to scale clearance (CL) from human hepatocyte and microsome CL(int) (intrinsic CL) for 52 drug compounds. By using the well-stirred model with protein binding included only 11% and 30% of the compounds were predicted within 2-fold and the average absolute fold errors (AAFE) for the predictions were 5.9 and 4.1 for hepatocytes and microsomes, respectively. When predictions were performed without protein binding, 59% of the compounds were predicted within 2-fold using either hepatocytes or microsomes and the AAFE was 2.2 and 2.3, respectively. For hepatocytes and microsomes there were significant correlations (P = 8.7 x 10(-13), R(2) = 0.72; P = 2.8 x 10(-9), R(2) = 0.61) between predicted CL(int in vivo) (obtained from in vitro CL(int)) and measured CL(int in vivo) (obtained using the well-stirred model). When CL was calculated from the regression, 76% and 70% of the compounds were predicted within 2-fold and the AAFE was 1.6 and 1.8 for hepatocytes and microsomes, respectively. We demonstrate that microsomes and hepatocytes are in many cases comparable when scaling of CL is performed from regression. By using the hepatocyte regression, CL for 82% of the compounds in an independent test set ...Continue Reading

References

Aug 1, 1981·Journal of Pharmacokinetics and Biopharmaceutics·L B Sheiner, S L Beal
May 1, 1994·Biopharmaceutics & Drug Disposition·B A Hoener
Jul 1, 1993·Pharmaceutical Research·B Davies, T Morris
Jan 9, 1998·Drug Metabolism Reviews·J B Houston, D J Carlile
Jul 19, 2002·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Yoshihiro ShibataYasuyuki Ishii
Mar 19, 2003·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Robert HouleJose M Silva
Apr 16, 2003·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Yoichi NaritomiYuichi Sugiyama
Jun 7, 2003·Toxicology and Applied Pharmacology·Esther F A BrandonJan H M Schellens
Jun 10, 2003·Clinical Pharmacokinetics·Collen M MasimirembwaTommy B Andersson
Aug 3, 2004·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Dermot F McGinnityRobert J Riley
Mar 25, 2005·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·N BlanchardP Coassolo
Jun 4, 2005·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Robert J RileyR P Austin
Mar 23, 2006·Drug Metabolism and Disposition : the Biological Fate of Chemicals·David Hallifax, J Brian Houston
Aug 26, 2006·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Anna-Karin Sohlenius-Sternbeck
Nov 30, 2006·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Hayley S BrownJ Brian Houston
Feb 3, 2007·Chemico-biological Interactions·Albert P Li
Jul 11, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Stefan S De BuckRon A H J Gilissen
Jul 20, 2007·The Journal of Pharmacy and Pharmacology·Urban Fagerholm
Jul 25, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Huadong TangEric Fluhler
Apr 16, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Peter J KilfordAleksandra Galetin
Apr 23, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·R Scott ObachNigel J Waters
Jan 21, 2009·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Paulo PaixãoJosé A G Morais
Jul 23, 2009·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·E FlobyA-K Sohlenius-Sternbeck

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Citations

Oct 21, 2011·Pharmaceutical Research·Ken-ichi Umehara, Gian Camenisch
Jan 18, 2012·Journal of Medicinal Chemistry·Jason G KettleSabina C Cosulich
Sep 1, 2011·Drug Metabolism and Pharmacokinetics·Haruka NishimutaSetsuko Komuro
Mar 6, 2013·Canadian Journal of Physiology and Pharmacology·Jian YinQin Meng
Dec 30, 2015·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Michelle SchaeferRoderich D Süssmuth
Feb 14, 2016·Environmental Toxicology and Pharmacology·Alessandra PirovanoA Jan Hendriks
Jan 15, 2013·Journal of Pharmaceutical Sciences·Johan Bylund, Tjerk Bueters
Dec 18, 2014·ACS Medicinal Chemistry Letters·Rebecca FranssonAnja Sandström
Apr 23, 2013·Environmental Toxicology and Chemistry·Kristin A ConnorsBryan W Brooks
Apr 11, 2013·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Sanja JuricAnna-Karin Sohlenius-Sternbeck
Aug 8, 2012·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Johan BylundStefan Czene
Apr 19, 2012·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Anna-Karin Sohlenius-SternbeckLovisa Afzelius
Jan 18, 2013·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Anna-Karin Sohlenius-SternbeckJohan Bylund
Jan 3, 2013·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Tjerk BuetersJohan Bylund
Sep 18, 2013·Drug Metabolism and Pharmacokinetics·Yoshihiro ShibataMasato Chiba
Mar 15, 2015·Toxicology in Vitro : an International Journal Published in Association with BIBRA·M-E WilleminC Brochot
Aug 26, 2016·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Tetsuo YamagataCarl Petersson
Aug 16, 2016·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Christine M Bowman, Leslie Z Benet
Apr 18, 2017·Journal of Pharmaceutical Sciences·Jingjing YuIsabelle Ragueneau-Majlessi
Jun 20, 2017·Environment International·Caroline L RingJohn F Wambaugh
Jan 24, 2018·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Yue LiFurong Qiu
Jan 8, 2014·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Patrik LundquistTommy B Andersson
Jan 8, 2014·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Gunilla EnglundDenis Projean
Aug 22, 2012·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Johan BylundTjerk Bueters
Mar 12, 2013·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Anders LindgrenTjerk Bueters
Jan 4, 2013·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Johan BylundAlexander Svanhagen
Mar 4, 2020·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Keiichi MoritaKiyomi Ito
Feb 24, 2015·Journal of Computer-aided Molecular Design·Susanne WiniwarterClaire Landqvist
Jun 7, 2020·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Tom S ChanMitchell E Taub

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