Vliv psychotropních látek na metabolickou aktivitu klinicky nejvýznamnjších izoenzym cytochromu p-450
| Title in English | Effect of psychotropic drubstances on metabolic activity on metabolic activity of clinically most important isoenzymes of cytochrome P-450 |
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| Authors | |
| Year of publication | 2004 |
| Type | Monograph |
| MU Faculty or unit | |
| Citation | |
| Description | The aim of presented Ph.D. thesis was to study the influence of psychotropic substances methamphetamine, fluoxetine, the combination of methamphetamine with fluoxetine and standardized extract LI 160 (Hypericum perforatum) on metabolic activity of clinically most important isoenzymes of cytochrome P-450. Experiments were performed on adult Wistar male rates both on intact animals and on the model of isolated perfused livers. The first part of the thesis showed the influence of methamphetamine, fluoxetine and their combination on pharmacokinetics of dextromethorphan and midazolam, the markers of a metabolic activity of isoenzymes CYP2D2 and CYP3A1/2. The most important finding was the significant increase of areas under curve of main metabolite of dextromethorphan (dextrorphan) and AUC of all detected metabolites of midazolam after the application of methamphetamine, which was in combination with inhibitive acting fluoxetine considerably antagonized. Our determined pharmacokinetic parameters of dextromethorphan and midazolam were similar to the previously published parameters of other authors. The second part of thesis realized on isolated perfused livers showed the significant effect of methamphetamine on hydroxylation of tolbutamide as an model reaction catalyzed by CYP2D6 and also on the O-demethylation of dextromethorphan a reaction catalyzed by CYP2D2. On the other hand, the statistically significant effect on hydroxylation of midazolam, a reaction catalyzed by isoenzyme CYP3A1/2 was not detected. An inhibitory influence of fluoxetine applied either alone or in the combination with methamphetamine on activities of each of the studied isoenzymes CYP2D6, CYP2D2, CYP3A1/2 was confirmed. In the final part dealing with the effects of standardized extract of St. Johns worth (LI 160) a statistically significant inhibitory effect on the activity of CYP2C6 was described, however the activity of isoenzymes CYP2D2 and CYP3A1/2 was significantly increased. From the result of our study came out, that mechanism of pharmacokinetic interactions of St. Johns worth extract does not imply the P-glycoprotein, but CYP3A1/2. Our findings demonstrating the influence of methamphetamine, a combination of methamphetamine with fluoxetine and standardized extract LI 160 on metabolic activity of most important isoenzymes of cytochrome P-450 can in the future contribute to the clinical practice, particularly in the area of substance abuse or to the pharmacotherapy of depressive disorders. Comparison of the results obtained in intact animal and on isolated organ confirmed that isolated perfused liver is a good experimental model for study of biotransformation reactions of substances, because obtained results respond to the results gained from an intact animal. |
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