Abstract
BackgroundOlanzapine (OLZ) is one of the most prescribed atypical antipsychotic drugs but its use is associated with unfavorable metabolic abnormalities. N-desmethyl-olanzapine (DMO), one of the OLZ metabolites by CYP1A2, has been reported to have a normalizing action on metabolic abnormalities, but this remains unclear. Our aim was to explore the correlation between the concentrations of OLZ or DMO with various metabolic parameters in schizophrenic patients.MethodsThe chromatographic analysis was carried out with a solvent delivery system coupled to a Coulochem III coulometric detector to determine OLZ and DMO simultaneously in OLZ-treated patients. The correlation between the concentration of OLZ or DMO and the metabolic parameters was analyzed by the Spearman rank order correlation method (r s).Principal FindingsThe established analytical method met proper standards for accuracy and reliability and the lower limitation of quantification for each injection of DMO or OLZ was 0.02 ng. The method was successfully used for the analysis of samples from nonsmoking patients (n = 48) treated with OLZ in the dosage range of 5–20 mg per day. There was no correlation between OLZ concentrations and tested metabolic parameters. DMO concentrations were negatively correlated with glucose (r s = –0.45) and DMO concentrations normalized by doses were also negatively correlated with insulin levels (r s = –0.39); however, there was a marginally positive correlation between DMO and homocysteine levels (r s = +0.38).ConclusionsThe observed negative correlations between levels of DMO and glucose or insulin suggest a metabolic normalization role for DMO regardless of its positive correlation with a known cardiovascular risk factor, homocysteine. Additional studies of the mechanisms underlying DMO’s metabolic effects are warranted.
Highlights
Olanzapine (LY170053; 2-methyl-4-(4-methyl-1-piperazinyl)10H- thieno[2,3b][1,5]benzodiazepine; OLZ) is a second-generation antipsychotic drug
OLZ is marketed as a neuroleptic with a low degree of extrapyramidal side effects [1,2], a recent study reported that patients treated with OLZ tended to develop various metabolic abnormalities when compared to the other atypical antipsychotics [3]
Chromatography selectivity and assay validation The run time of the assay was 30 minutes and the drugs were well resolved with retention times of 5.88 mins for DMO, 8.04 mins for OLZ and 26.27 mins for clozapine at a flow rate of 1 mL/min
Summary
Olanzapine (LY170053; 2-methyl-4-(4-methyl-1-piperazinyl)10H- thieno[2,3b][1,5]benzodiazepine; OLZ) is a second-generation antipsychotic drug. OLZ is marketed as a neuroleptic with a low degree of extrapyramidal side effects [1,2], a recent study reported that patients treated with OLZ tended to develop various metabolic abnormalities when compared to the other atypical antipsychotics [3]. Various smoking behaviors may influence the OLZ concentration and pharmacokinetic parameters [6,7] due to the increased activity of CYP1A2 associated with smoking. Olanzapine (OLZ) is one of the most prescribed atypical antipsychotic drugs but its use is associated with unfavorable metabolic abnormalities. N-desmethyl-olanzapine (DMO), one of the OLZ metabolites by CYP1A2, has been reported to have a normalizing action on metabolic abnormalities, but this remains unclear. Our aim was to explore the correlation between the concentrations of OLZ or DMO with various metabolic parameters in schizophrenic patients
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