title: Polymorphisms influencing olanzapine metabolism and adverse effects in healthy subjects.
abstract: 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.
authors.affiliation: Clinical Pharmacology Service, Hospital Universitario de la Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain. teresa.cabaleiro@salud.madrid.org
authors.forename: Teresa
authors.initials: T
authors.lastname: Cabaleiro
authors.forename: Rosario
authors.initials: R
authors.lastname: López-Rodríguez
authors.forename: Dolores
authors.initials: D
authors.lastname: Ochoa
authors.forename: Manuel
authors.initials: M
authors.lastname: Román
authors.forename: Jesús
authors.initials: J
authors.lastname: Novalbos
authors.forename: Francisco
authors.initials: F
authors.lastname: Abad-Santos
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D001569:Benzodiazepines / Q000009:adverse effects / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D056148:Chromatography, Reverse-Phase; D018592:Cross-Over Studies; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D000077152:Olanzapine; D020411:Oligonucleotide Array Sequence Analysis; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011388:Prolactin / Q000097:blood*; D060888:Real-Time Polymerase Chain Reaction; D012044:Regression Analysis; D012737:Sex Factors; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D001569:Benzodiazepines; D011388:Prolactin; D000077152:Olanzapine