The Influence of Long-Term Treatment with Asenapine on Liver Cytochrome P450 Expression and Activity in the Rat. The Involvement of Different Mechanisms
| Autor: | Ewa Bromek, Przemysław J Danek, Władysława A. Daniel |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
medicine.medical_specialty
CYP3A Pharmaceutical Science 030226 pharmacology & pharmacy Article cytochrome P450 expression 03 medical and health sciences chronic treatment Pharmacy and materia medica 0302 clinical medicine Blood serum Internal medicine Drug Discovery medicine Asenapine Testosterone Triiodothyronine biology business.industry CYP1A2 Cytochrome P450 enzyme activity RS1-441 Endocrinology rat liver asenapine biology.protein Medicine Molecular Medicine business 030217 neurology & neurosurgery medicine.drug Hormone |
| Zdroj: | Pharmaceuticals Volume 14 Issue 7 Pharmaceuticals, Vol 14, Iss 629, p 629 (2021) |
| ISSN: | 1424-8247 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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