Carriers of the UGT1A4 142T>G gene variant are predisposed to reduced olanzapine exposure—an impact similar to male gender or smoking in schizophrenic patients
- 9 February 2010
- journal article
- research article
- Published by Springer Science and Business Media LLC in European Journal of Clinical Pharmacology
- Vol. 66 (5), 465-474
- https://doi.org/10.1007/s00228-009-0783-8
Abstract
Purpose The impact of the UGT1A4, CYP1A2, and MDR1 genetic variants on olanzapine plasma levels, in relation to those of other individual factors, such as gender, smoking status, body weight, and age, was investigated in patients with schizophrenia. Methods A total of 121 patients were recruited from psychosis-specialized outpatient departments in Stockholm County. Olanzapine plasma concentrations were determined by high-performance liquid chromatography. Genotyping was carried out by PCR-restriction fragment length polymorphism or minisequencing, and haplotypes were analyzed using specialized computer software on population genetics. Multiple regression analysis was performed to investigate the combined effect of patient characteristics and genotypes/haplotypes on daily dose-corrected plasma concentrations of olanzapine. Results In addition to , the results indicate that inter-patient differences in olanzapine exposure were explained by the known factor of time of sampling from last dose intake and by the following individual factors in order of relative impact: (1) male gender, (2) carrier of the UGT1A4 142T>G single nucleotide polymorphism (SNP), and (3) smoking. Each of these three factors predicted a decrease in daily dose-corrected plasma concentrations of 35, 25, and 21%, respectively. In contrast, age, body weight, and MDR1 or CYP1A2 haplotype did not have a significant impact. Conclusions At 12 h after dose intake, the regression model predicted a 5.1-fold higher olanzapine plasma level in a non-smoking female patient who did not carry the UGT1A4 142T>G SNP compared to a smoking man treated with the same dose but heterozygous for UGT1A4 142T>G SNP. Whether these combined genetic and environmental factors influence the risk of therapeutic failure remains to be established.Keywords
This publication has 20 references indexed in Scilit:
- Large Intraindividual Variability of Olanzapine Serum Concentrations in Adolescent PatientsTherapeutic Drug Monitoring, 2008
- Associations between MDR1 gene polymorphisms and schizophrenia and therapeutic response to olanzapine in female schizophrenic patientsJournal of Psychiatric Research, 2008
- Induction of CYP1A2 by heavy coffee consumption in Serbs and SwedesEuropean Journal of Clinical Pharmacology, 2007
- Comparisons of CYP1A2 genetic polymorphisms, enzyme activity and the genotype-phenotype relationship in Swedes and KoreansEuropean Journal of Clinical Pharmacology, 2007
- UDP-GLUCURONOSYLTRANSFERASE 1A4 POLYMORPHISMS IN A JAPANESE POPULATION AND KINETICS OF CLOZAPINE GLUCURONIDATIONDrug Metabolism and Disposition, 2005
- Clinical outcome and olanzapine plasma levels in acute schizophreniaEuropean Psychiatry, 2005
- Variation of hepatic glucuronidation: Novel functional polymorphisms of the UDP-glucuronosyltransferase UGT1A4Hepatology, 2004
- Glucuronidation of olanzapine by cDNA‐expressed human UDP‐glucuronosyltransferases and human liver microsomesHuman Psychopharmacology: Clinical and Experimental, 2002
- Olanzapine: an atypical antipsychotic for schizophreniaExpert Opinion on Pharmacotherapy, 2000
- Identification of the human cytochromes P450 responsible for the in vitro formation of the major oxidative metabolites of the antipsychotic agent olanzapine.1996