Olanzapine in serum and cerebrospinal fluid in patients with schizophrenia or schizoaffective disorder

• Background:  The relationship  between serum and CSF concentrations  of olanzapine  (OLA)  in humans  has  to our  knowledge not been described earlier. Few studies have investigated how the CYP2D6 and CYP1A2 polymorphisms affect OLA pharmacoki- netics in humans [1] [2]. Polymorphisms in the ABCB1 gene have been associated with altered pharmacokinetics of certain drugs including risperidone [3].The aim of the present study was to investigate the relationship between steady state serum and cerebrospinal fluid (CSF) con- centrations of OLA and its metabolite 4t -N-desmethylolanzapine (DMO) and to address the influence  of smoking,  gender, age as well as polymorphisms in genes coding for OLA metabolism (CYP2D6, CYP1A2) and transport (ABCB1) in patients with schizophrenia  or schizoaffective  disorder, treated with oral OLAas the only antipsychotic  drug.Methods: Thirty seven Caucasian outpatients (10 smokers and27 non-smokers),  suffering from schizophrenia or schizoaffective disorder according to DSM-IV criteria were included in the study. From 29 out of them, CSF was collected successfully.Fasting blood samples were collected in the morning for analy- ses of OLA and DMO and for genotyping (polymorphisms of CYP2D6,  CYP1A2  and  ABCB1).  Lumbar  puncture  was  per- formed  at close  connection  to blood  sampling  at the minimum of eight hours in the fasting state. The blood and CSF samples were stored at −70ºC until analysed.A validated accurate and sensitive LC-MS/MS method was used for the analysis of OLA and DMO. Analytes were quantified  by using linear gradient reversed phase chromatography with tandem mass  spectrometry  detection  operating  in  positive  electro-sprayionization mode with multiple reactions monitoring (MRM).Results:  A  strong  correlation  (rs =0.93;  p < 0.05)  was  foundbetween serum and CSF concentrations  of OLA and a somewhatweaker (rs =0.5; p < 0.05) between those of DMO. The CSF con- centrations  of  OLA  and  DMO  were  in  average  13%  and  16% of those in serum. Extensive metabolizers of CYP2D6 were pre- scribed higher (p < 0.05) daily doses than poor metabolizers when the influence of smoking habits was taken into account. Smokers had  lower  concentration-to-dose   ratios  (C/D)  of  OLA  both  in serum and CSF than non-smokers  (median  7 vs. 10 nmol/L/mg in serum and 0.8 vs. 1.3 nmol/L/mg  in CSF; p < 0.01). C/D for serum DMO decreased with increasing age (rs = −0.41; p < 0.05). Carriers of ABCB1 1236T/2677T/3435T haplotype had higher serum (median 112 vs. 80 nmol/L; p < 0.05) and CSF (13.7 vs. 8.1 nmol/L; p < 0.05) OLA concentrations  than patients without this haplotype. Patients treated with benzodiazepines and/or zopiclone (n = 8) had higher DMO and DMO/OLA ratio (p < 0.05 for both) in CSF compared to patients not co-medicating  with these drugs (n = 21), even when smoking habits were taken into account.Conclusion:  The present study shows a very good correlation between  serum and CSF concentrations  of OLA, indicating  thatconcentrations  of OLA in serum reflect the situation in CSF.References[1]  Hägg S, Spigset O, Lakso H, et al. Olanzapine disposition in humans is unrelated to CYP1A2 and CYP2D6 phenotypes. Eur J Clin Pharmacol2001;57:493−97.[2]  Carrillo  JA, Herra´iz  AG, Ramos SI, et al. Role of smoking-inducedcytochrome P450 (CYP)1A2 and polymorphic CYP2D6 in steady-stateconcentration of olanzapine. J Clin Psychopharmacol 2003;23:119−27.[3]  Gunes A, Spina E, Dahl M-L, et al. ABCB1 polymorphisms influencesteady-state  plasma  levels  of  9-hydroxyrisperidone   and  risperidoneactive moiety. Ther Drug Monit 2008;30:628−33.

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