Abstract 1680: Characterization of olanzapine glucuronidation: Potential role of the UGT2B10 codon 67 SNP in olanzapine metabolism

Abstract

Abstract Olanzapine (OLZ) is an atypical antipsychotic with broad applications for cancer patients including treatment-resistant depression, psychiatric problems such as schizophrenia or bipolar disorder, and chemotherapy-induced nausea and vomiting. The half-life of OLZ varies widely between patients. The purpose of the present study was to determine the relative contribution of various UDP-glucuronosyltransferases (UGTs) that are known to metabolize OLZ and examine the role of functional UGT genetic variants as a potential determinant of OLZ metabolism. OLZ glucuronides were identified by ultra-pressure liquid chromatography (UPLC) and the UGTs exhibiting activity against OLZ were determined using homogenates of UGT-over-expressing HEK293 cell lines. Kinetic analysis was performed for active wild-type and variant UGTs. The clinical and physiological relevance of polymorphic active UGTs was examined by studying OLZ metabolism in 114 human liver microsomes and characterizing their glucuronidation activity via UPLC. One-Way ANOVA using Tukey's family error rate was used for pairwise comparisons between cell lines. Student's 2-sample t-test was used to compare human liver microsome glucuronidation data. UPLC analysis of cell line homogenate samples revealed three distinct glucuronidation products. We found that two UGT enzymes, UGT1A4 and UGT2B10, exhibit glucuronidation activity against OLZ. The enzymatic activity of UGT1A4 codon 24 and codon 48 variants against OLZ was significantly different from wild-type UGT1A4 (both p < 0.05). In addition, the UGT2B1067Tyr variant exhibited no glucuronidation activity against OLZ. Human liver microsomes homozygous for the UGT2B1067Tyr variant exhibited an 82% reduction in glucuronidation activity against OLZ (p<0.05). These data demonstrate the significance of a previously unrecognized UGT (UGT2B10) in OLZ excretion and the potential importance of a functional SNP at codon 67 of the UGT2B10 gene in the wide variability observed in OLZ metabolism between individuals. This could have an important impact on overall patient response/toxicity to OLZ. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1680.