In Vitro Characterization of the Human Liver Microsomal Kinetics and Reaction Phenotyping of Olanzapine Metabolism

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Porntipa KorprasertthawornAndrew Rowland

Abstract

Olanzapine (OLZ) is an atypical antipsychotic used in the treatment of schizophrenia and related psychoses. The metabolism of OLZ is complex and incompletely characterized. This study aimed to elucidate the enzymes and pathways involved in the metabolism of OLZ and to determine the kinetics of OLZ oxidation and glucuronidation by human liver microsomes, recombinant cytochrome P450 (rP450) enzymes, and recombinant UDP-glucuronosyltransferase (rUGT) enzymes. An ultra-performance liquid chromatography-mass spectrometry method was developed and validated to quantify OLZ, its four oxidative metabolites (N-desmethyl-OLZ, 2-hydroxymethyl-OLZ, 7-hydroxy-OLZ, and OLZ-N-oxide), and two N-glucuronides (OLZ-10-N-glucuronide and OLZ-4'-N-glucuronide). Consistent with previous reports, UGT1A4, CYP1A2, and flavin-containing monooxygenase 3 play major roles in catalyzing the formation of OLZ-10-N-glucuronide, 7-hydroxy-OLZ, and OLZ-N-oxide, respectively. In addition, a previously uncharacterized major contribution of CYP2C8 to OLZ-N-demethylation was demonstrated. The kinetics of OLZ metabolite formation (Km and Vmax) by human liver microsomes, rP450 enzymes, and rUGT enzymes were characterized in the presence of bovine serum albumin [2% (w/v)...Continue Reading

References

Jan 1, 1991·Pharmacology & Therapeutics·J O Miners, P I Mackenzie
Oct 6, 1999·British Journal of Clinical Pharmacology·S J BaldwinR J Chenery
May 3, 2000·British Journal of Clinical Pharmacology·J A McLureD J Birkett
Nov 9, 2001·European Journal of Clinical Pharmacology·S HäggR Dahlqvist
Mar 18, 2003·Journal of Clinical Psychopharmacology·Juan Antonio CarrilloJulio Benítez
Mar 20, 2003·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Kara Lee ShirleyMichael W Jann
Dec 4, 2003·JAMA : the Journal of the American Medical Association·Robert RosenheckUNKNOWN Department of Veterans Affairs Cooperative Study Group on the Cost-Effectiveness of Olanzapine
Jan 27, 2004·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·S L BoyeD J Birkett
Nov 20, 2004·Pharmacopsychiatry·P BaumannUNKNOWN Arbeitsge-meinschaft fur neuropsychopharmakologie und pharmakopsychiatrie
May 19, 2005·Clinical Pharmacology and Therapeutics·Rheem A Totah, Allan E Rettie
Mar 28, 2006·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Andrew RowlandJohn O Miners
Sep 19, 2006·Life Sciences·Hsien-Tsung YaoTeng-Kuang Yeh
Mar 2, 2010·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Suresh Babu NaraharisettiRheem A Totah
Jun 10, 2011·Clinical Pharmacokinetics·Erin SchwengerMary H H Ensom
Jul 14, 2011·Pharmacogenetics and Genomics·Kathryn Kelly Erickson-RidoutPhilip Lazarus
Oct 15, 2011·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Michael H CourtMoshe Finel
Feb 15, 2012·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Nitsupa WattanachaiJohn O Miners
Mar 16, 2013·Pharmacogenetics and Genomics·Mao M SöderbergMarja-Liisa Dahl
Mar 19, 2013·The International Journal of Biochemistry & Cell Biology·Andrew RowlandPeter I Mackenzie
Apr 25, 2013·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Yukiko KatoMiki Nakajima

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Citations

Sep 30, 2016·Expert Opinion on Drug Metabolism & Toxicology·Ian R Phillips, Elizabeth A Shephard
Aug 9, 2017·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Barry C JonesDanxi Li
Jul 19, 2019·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Ian R Phillips, Elizabeth A Shephard
Dec 2, 2017·British Journal of Clinical Pharmacology·Thomas M PolasekAndrew Rowland
Dec 10, 2017·Hematology·Tal Gazitt, Thomas P Loughran
Aug 20, 2019·Therapeutic Drug Monitoring·Igor I MiroshnichenkoNatalia V Baymeeva
Jan 2, 2016·Pharmacological Reviews·Janne T BackmanPertti J Neuvonen
Jul 28, 2020·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Wei WangDonglu Zhang
Jun 5, 2020·British Journal of Clinical Pharmacology·Anil R MaharajChristoph P Hornik
Nov 28, 2020·Current Treatment Options in Oncology·Mellar P Davis, Gareth J Sanger
Jan 1, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Pablo ZubiaurFrancisco Abad-Santos
Dec 29, 2020·Frontiers in Genetics·Beatriz Carvalho HenriquesKatherine J Aitchison
Apr 6, 2021·EBioMedicine·Sofia CussottoBrendan T Griffin
Sep 17, 2021·Pharmacogenomics·Pablo ZubiaurFrancisco Abad-Santos

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