title: Olanzapine metabolism and the significance of UGT1A448V and UGT2B1067Y variants.
abstract: OBJECTIVE
  Olanzapine is an antipsychotic used in the treatment of schizophrenia, bipolar disorder, and treatment-resistant depression. Glucuronidation by the UDP-glucuronosyltransferase (UGT) family of enzymes is the major mode of olanzapine metabolism, and polymorphisms in these enzymes could contribute to interindividual variability in olanzapine metabolism and therapeutic response.
  
  
  METHODS
  Cell lines overexpressing individual UGT enzymes were used to determine which UGTs have enzymatic activity against olanzapine, characterize the kinetics of this reaction, and examine the effects of UGT variants on olanzapine metabolism. A bank of 105 human liver microsomes (HLM) were used to perform a phenotype-genotype study comparing glucuronidation activity against UGT genotype.
  
  
  RESULTS
  Cell lines overexpressing the individual UGTs 1A4 and 2B10 exhibited glucuronidation activity against olanzapine. The UGT1A4 variant exhibited a 3.7-fold (P<0.0001) higher Vmax/KM for the formation of the olanzapine-10-N-glucuronide isomer 1, and a 4.3-fold (P<0.0001) higher Vmax/KM for the formation of the olanzapine-10-N-glucuronide isomer 2 than wild-type UGT1A4. The UGT2B10 variant exhibited no glucuronidation activity against olanzapine. In a screening of 105 HLM specimens, there was a 2.1-fold (P=0.04) and 1.6-fold (P=0.0017) increase in the rate of olanzapine-10-N-glucuronide isomer 1 and olanzapine-4'-N-glucuronide formation, and a 2-fold (P=0.02) increase in the overall olanzapine glucuronidation formation, in HLM with the UGT1A4 (*3/*3)/UGT2B10 (*1/*1) genotype compared with HLM with the UGT1A4 (*1/*1)/UGT2B10 (*1/*1) genotype. There was a 1.9-fold (P<0.003) decrease in the formation of both isomers of the olanzapine-10-N-glucuronide, a 2.7-fold (P<0.0001) decrease in olanzapine-4'-N-glucuronide formation, and a 2.1-fold (P=0.0002) decrease in the overall olanzapine glucuronide formation in HLM with at least one UGT2B10*2 allele. In regression analysis, the UGT1A4*3 (P<0.02) and UGT2B10*2 (P<0.002) alleles were significant predictors of the formation of all olanzapine glucuronide isomers.
  
  
  CONCLUSIONS
  The UGTs 1A4 and 2B10 glucuronidate olanzapine and functional variants of these UGTs significantly alter olanzapine glucuronidation in vitro. These data suggest that the UGT1A4*3 and UGT2B10*2 alleles contribute significantly to interindividual variability in olanzapine metabolism.
authors.affiliation: Department of Pharmacology, Pennsylvania State College of Medicine, Hershey, PA 17033, USA.
authors.forename: Kathryn Kelly
authors.initials: KK
authors.lastname: Erickson-Ridout
authors.forename: Junjia
authors.initials: J
authors.lastname: Zhu
authors.forename: Philip
authors.initials: P
authors.lastname: Lazarus
mesh_terms: D014150:Antipsychotic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001569:Benzodiazepines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological; D001714:Bipolar Disorder / Q000188:drug therapy / Q000235:genetics; D002460:Cell Line; D061218:Depressive Disorder, Treatment-Resistant / Q000188:drug therapy / Q000235:genetics; D056726:Genetic Association Studies; D014644:Genetic Variation; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver; D000077152:Olanzapine; D020641:Polymorphism, Single Nucleotide; D012044:Regression Analysis; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics
chemical_list: D014150:Antipsychotic Agents; D054316:Biomarkers, Pharmacological; C019787:bilirubin glucuronoside glucuronosyltransferase; D001569:Benzodiazepines; C552162:UGT2B10 protein, human; D014453:Glucuronosyltransferase; D000077152:Olanzapine