Abstract
Therapy of schizophrenia requires long-term treatment with a relevant antipsychotic drug to achieve a therapeutic effect. The aim of the present study was to investigate the influence of prolonged treatment with the atypical neuroleptic asenapine on the expression and activity of rat cytochrome P450 (CYP) in the liver. The experiment was carried out on male Wistar rats. Asenapine (0.3 mg/kg s.c.) was administered for two weeks. The levels of CYP mRNA protein and activity were determined in the liver and hormone concentrations were measured in the pituitary gland and blood serum. Asenapine significantly decreased the activity of CYP1A (caffeine 8-hydroxylation and 3-N-demethylation), CYP2B, CYP2C11 and CYP3A (testosterone hydroxylation at positions 16β; 2α and 16α; 2β and 6β, respectively). The neuroleptic did not affect the activity of CYP2A (testosterone 7α-hydroxylation), CYP2C6 (warfarin 7-hydroxylation) and CYP2E1 (chlorzoxazone 6-hydroxylation). The mRNA and protein levels of CYP1A2, CYP2B1, CYP2C11 and CYP3A1 were decreased, while those of CYP2B2 and CYP3A2 were not changed. Simultaneously, pituitary level of growth hormone-releasing hormone and serum concentrations of growth hormone and corticosterone were reduced, while that of triiodothyronine was enhanced. In conclusion, chronic treatment with asenapine down-regulates liver cytochrome P450 enzymes, which involves neuroendocrine mechanisms. Thus, chronic asenapine treatment may slow the metabolism of CYP1A, CYP2B, CYP2C11 and CYP3A substrates (steroids and drugs). Since asenapine is metabolized by CYP1A and CYP3A, the neuroleptic may inhibit its own metabolism, therefore, the plasma concentration of asenapine in patients after prolonged treatment may be higher than expected based on a single dose.
Highlights
Cytochrome P450 (CYP) enzymes are members of the superfamily of heme-containing monooxygenases that catalyze the metabolism of endogenous substances and the majority of clinically important drugs including psychotropics [1,2]
CYP3A, the neuroleptic may inhibit its own metabolism, the plasma concentration of asenapine in patients after prolonged treatment may be higher than expected based on a single dose
The effect of the chronicoftreatment of activities asenapine on activities of different cytochrome as the rates of CYP-specific reactions in rat liver microsomes: caffeine 8-hydroxylation and 3-N-demethylation (CYP1A), P450 enzymes, measured as the rates of CYP-specific reactions in rat liver microsomes: caffeine testosterone 7α- (CYP2A), 16β- (CYP2B), 2α- and 16α- (CYP2C11), and 2β- and 6β- (CYP3A) hydroxylation, warfarin 78-hydroxylation (CYP1A), testosterone (CYP2A), 16β-as(CYP2B), and
Summary
Cytochrome P450 (CYP) enzymes are members of the superfamily of heme-containing monooxygenases that catalyze the metabolism of endogenous substances (e.g., steroids, monoaminergic neurotransmitters, arachidonic acid, bile acids) and the majority of clinically important drugs including psychotropics (neuroleptics, antidepressants, anxiolytics) [1,2]. Among various CYP enzymes, CYP1, CYP2 and CYP3 are three major families that are involved in the metabolism of approximately 90% of drugs on the market [2]. Drugs that can inhibit or induce the metabolic activity of the CYP enzymes have the potential to affect the metabolism of concomitantly administered drugs, and to lead to changes in their efficacy or to increase the risk of adverse effects [3,4,5,6]. CYP inhibitors, such as 1-aminobenzotriazole or atipamezole (pan-specific), are useful tools for discovering CYP-governed metabolism of newly projected drugs or pharmacological tools, and for showing the influence of the enzyme on drug pharmacokinetics [7,8,9,10,11].
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