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Life sciences

Acute effects of oral olanzapine treatment on the expression of fatty acid and cholesterol metabolism-related gene in rats.


PMID 25744410

Abstract

Second-generation antipsychotic drugs (SGAs) have a high risk for serious metabolic side-effects including dyslipidemia. This study aimed to investigate the acute effects of oral olanzapine treatment on the expression of genes for fatty acid and cholesterol biosynthesis in rats. Female Sprague-Dawley rats were treated orally with olanzapine (1mg/kg, equivalent to a human clinical dose of 10mg) via self-administration aimed to measure pharmacokinetics. Based on the pharmacokinetic analysis, the acute effects of olanzapine on sterol regulatory element binding protein (SREBP)-related fatty acid/cholesterol metabolism genes were investigated in the liver and perirenal white adipose tissue (WAT) by Real-time quantitative PCR. A pharmacokinetic analysis demonstrated that the maximum concentration of olanzapine in plasma (Cmax) occurred at 6h with a peak concentration of 276.5ng/ml after a single oral treatment and with a plasma elimination half-life of 3.5h after peak. The mRNA expression of SREBP-2 and target genes for cholesterol synthesis and transport was increased 1.9 8.8 fold compared with the control at 6h after olanzapine administration but returned to basal level at 12h post-treatment, while the increased mRNA expression of SREBP-1c and its targeted fatty acid-related genes appeared at both 6h and 12h post-treatment. The present study provided evidence that olanzapine at a clinically-relevant dose caused abnormal expression of genes involved in lipid metabolism in the liver and WAT. These results suggest that olanzapine may cause dyslipidemia side-effects through direct effects on lipid biosynthesis and efflux genes associated with SREBP-stimulated transcriptional changes.

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O1141
Olanzapine, ≥98% (HPLC)
C17H20N4S