RT Journal Article
SR Electronic
T1 In Vitro Characterization of Human Liver Microsomal Kinetics and Enzyme Involvement in Olanzapine Metabolism
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.115.064790
DO 10.1124/dmd.115.064790
A1 Porntipa Korprasertthaworn
A1 Thomas M Polasek
A1 Michael J Sorich
A1 Andrew J McLachlan
A1 John O Miners
A1 Geoffrey Tucker
A1 Andrew Rowland
YR 2015
UL http://dmd.aspetjournals.org/content/early/2015/09/01/dmd.115.064790.abstract
AB Olanzapine (OLZ) is an atypical antipsychotic used in the treatment of schizophrenia and related psychoses. The metabolism of OLZ is complex and incompletely characterized. The aim of this study was 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 (HLMs), and recombinant cytochrome P450 (rCYP) and recombinant UDP-glucuronosyltransferase (rUGT) enzymes. A UPLC-MS 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 HLMs, rCYP and rUGT enzymes were characterized in the presence of bovine serum albumin (BSA; 2% w/v). Consistent with the known effect of BSA on CYP1A2, CYP2C8 and UGT1A4 activities, Km values reported here are lower than previously reported values for OLZ metabolic pathways. In addition to CYP1A2-mediated OLZ-N-demethylation, these results suggest that other CYP enzymes, particularly CYP2C8, contribute significantly to oxidative OLZ metabolism through catalysis of OLZ-N-demethylation.