Vliv metamfetaminu na biotransformační procesy cytochromu P450
| Title in English | Influence of methamphetamine on CYP450 |
|---|---|
| Authors | |
| Year of publication | 2005 |
| Type | Article in Periodical |
| Magazine / Source | Adiktologie |
| MU Faculty or unit | |
| Citation | |
| Field | Pharmacology and pharmaceutical chemistry |
| Keywords | Methamphetamine; Liver; Isolated perfused; CYP2C; CYP2D; CYP3A; |
| Description | Methamphetamine is the fourth most frequently cited drug of abuse on treatment centers admission records behind cocaine, heroin and marijuana. The present study was undertaken to investigate the possible influence of methamphetamine on pharmacokinetics of tolbutamide as a model substrate for rat CYP2C6, dextromethorphan for rat CYP2D2 and midazolam for CYP3A1/2. Experiments were performed in adult Wistar male rats, both in intact animals and on the model of their isolated perfused livers. The results of pharmacokinetic analysis have shown significantly increased rates of dextrorphane and 3-hydroxymorphinan formation, which indicate a stimulatory effect of methamphetamine on CYP2D2 metabolic activity. Similarly, the kinetics of midazolam metabolic conversion to its hydroxyderivatives indicated a significant increase in CYP3A1/2 activity. The second part of experiments performed on isolated perfused livers showed the significant effect of methamphetamine on hydroxylation of tolbutamide and also on O-demethylation of dextromethorphan. On the other hand, the statistically significant effect on CYP3A1/2-mediated hydroxylation of midazolam, observed in in vivo experiments, was not confirmed on the isolated liver. Our findings demonstrating the influence of methamphetamine on metabolic activity of the most important isoenzymes of cytochrome P-450 can contribute to the clinical practice in the future, particularly in the area of substance abuse. Comparison of the results obtained from experiments in intact animals and in isolated organs has confirmed that the isolated perfused liver can be used as a suitable experimental model for studies of biotransformation reactions of drugs and other xenobiotics. |
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