Polymorphisms influencing olanzapine metabolism and adverse effects in healthy subjects

• Published in: Human psychopharmacology Vol. 28; no. 3; pp. 205 - 214
• Main Authors: Cabaleiro, Teresa, López-Rodríguez, Rosario, Ochoa, Dolores, Román, Manuel, Novalbos, Jesús, Abad-Santos, Francisco
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.05.2013; Wiley Subscription Services, Inc
• Subjects: Adult; adverse effects; Antipsychotic Agents - adverse effects; Antipsychotic Agents - pharmacokinetics; Benzodiazepines - adverse effects; Benzodiazepines - pharmacokinetics; Chromatography, High Pressure Liquid; Chromatography, Reverse-Phase; Cross-Over Studies; Dopamine D2 receptors; Female; Genetic Variation; Humans; Male; olanzapine; Oligonucleotide Array Sequence Analysis; pharmacodynamics; Pharmacogenetics; pharmacokinetics; Polymorphism, Genetic; Prolactin - blood; Real-Time Polymerase Chain Reaction; Regression Analysis; Sex Factors; Tandem Mass Spectrometry; Young Adult
• ISSN: 0885-6222; 1099-1077; 1099-1077
• DOI: 10.1002/hup.2308

Objective The pharmacokinetics of olanzapine and response to treatment could be affected by polymorphisms in genes coding for drug‐metabolizing enzymes, transporters, or receptors. The aim of this study was to identify genetic markers predictive of pharmacokinetics, pharmacodynamics, and adverse effects of olanzapine. Methods Sixty‐three healthy volunteers receiving a single 5‐mg oral dose of olanzapine were genotyped for 39 genetic variants that could be related to the response to olanzapine. All genetic variants were analyzed by PharmaChip, but DRD2 Taq1A polymorphism was determined by real‐time polymerase chain reaction. Olanzapine was measured using high‐performance liquid chromatography combined with tandem mass spectrometry. The relationship of gender and polymorphisms with olanzapine pharmacokinetics, the change in prolactin levels, and the incidence of adverse effects were evaluated by multiple regression analysis. Results The pharmacokinetics of olanzapine was influenced by polymorphisms in CYP3A5, GSTM3, and GRIN2B. Prolactin levels were affected by gender and polymorphisms in DRD2 and 5‐HTR2A. Polymorphisms in CYP2C9, TPMT, UGT1A1, MDR1, and 5‐HTR2A were related to some adverse effects of olanzapine. Conclusions Several polymorphisms can explain differences in the pharmacokinetics, pharmacodynamics, and safety of olanzapine in healthy subjects. Whether these genetic factors influence the risk of therapeutic failure or tolerability in patients remains to be established. Copyright © 2013 John Wiley & Sons, Ltd.