title: Valproic Acid significantly lowers serum concentrations of olanzapine-an interaction effect comparable with smoking.
abstract: BACKGROUND
  Preliminary reports have indicated that valproic acid (VPA) reduces serum concentrations of olanzapine (OLZ). The aim of this study was to investigate the impact of VPA and other antiepileptic drugs (AEDs) on serum concentrations of OLZ and 3 of its major metabolites in a large-scale material of therapeutic drug monitoring samples.
  
  
  METHODS
  OLZ-treated patients were stratified into subgroups according to coadministration of various AEDs, that is, lamotrigine (LTG; 110 patients/153 samples), VPA (92/166), LTG + VPA (7/12), carbamazepine (CBZ) (8/8), oxcarbazepine (2/3), gabapentin (3/4), levetiracetam (2/3), and topiramate (2/2). A control group treated with OLZ without AEDs was also included (205/247). Dose-adjusted serum concentrations (C:D ratios) of OLZ and its major metabolites (N-desmethyl, N-oxide, and 10-N-glucuronide) were compared between AED subgroups and controls, using linear mixed model analyses with age, gender, and cigarette smoking as covariates.
  
  
  RESULTS
  Significantly lower OLZ C:D ratios were found in patients comedicated with VPA (-32%, P < 0.001), VPA + LTG (-31%, P < 0.01), and CBZ (-50%, P < 0.001), compared with controls. The 10-N-glucuronide concentration was significantly lower in patients comedicated with VPA (-26%, P < 0.001), whereas CBZ significantly lowered N-desmethyl (-42%, P = 0.001) and N-oxide (-52%, P < 0.001) metabolite concentrations. C:D ratios of OLZ and metabolites were not significantly affected by comedication with LTG or any of the other AEDs. All covariates were significant determinants of OLZ C:D ratio, that is, age 60 years or above +35% (P < 0.001), female gender +11% (P < 0.01) and smoking -32% (P < 0.001).
  
  
  CONCLUSIONS
  Concurrent use of VPA significantly decreases serum concentrations of OLZ to an extent comparable with smoking. The mechanism behind the interaction could not be derived from the results of this study.
authors.affiliation: Center for Psychopharmacology, Diakonhjemmet Hospital, School of Pharmacy, University of Oslo, Oslo, Norway. tore.haslemo@diakonsyk.no
authors.forename: Tore
authors.initials: T
authors.lastname: Haslemo
authors.forename: Kristine
authors.initials: K
authors.lastname: Olsen
authors.forename: Hilde
authors.initials: H
authors.lastname: Lunde
authors.forename: Espen
authors.initials: E
authors.lastname: Molden
mesh_terms: D000328:Adult; D000367:Age Factors; D000927:Anticonvulsants / Q000627:therapeutic use; D001569:Benzodiazepines / Q000097:blood* / Q000378:metabolism / Q000627:therapeutic use*; D004347:Drug Interactions; D016903:Drug Monitoring / Q000379:methods; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D012189:Retrospective Studies; D012907:Smoking / Q000097:blood; D014635:Valproic Acid / Q000627:therapeutic use*
chemical_list: D000927:Anticonvulsants; D001569:Benzodiazepines; D014635:Valproic Acid; D000077152:Olanzapine