Methamphetamine-induced changes in the activities of drug-metabolizing enzymes: "in vivo - in vitro" correlation studies
| Authors | |
|---|---|
| Year of publication | 2006 |
| Type | Article in Proceedings |
| Conference | Monitoring Molecules in Neuroscience |
| MU Faculty or unit | |
| Citation | |
| Field | Pharmacology and pharmaceutical chemistry |
| Keywords | methamphetamine; drug metabolism; pharmacokinetics; liver perfusion; rat; |
| Description | The aim of the present study was to ascertain the influence of MET on activities of rat isoforms of CYP enzymes, mainly of CYP2C, CYP2D and CYP3A. In order to comprise the complexity of the possible pharmacokinetic changes evoked by methamphetamine, several series of experiments on various models and levels were performed in Wistar rats treated with MET: 1) the pharmacokinetic study in vivo; 2) the study on the isolated perfused rat liver; 3) the study on the rat liver microsomes. The results obtained in the isolated perfused rat liver confirmed the stimulatory effect of MET treatment on the CYP2D enzyme subfamily as it was observed in the in vivo experiments; AUC of dextromethorphan was significantly decreased (p<0.001) but Cl of dextromethorphan was significantly increased. Concurrently, the AUC of the O-demethylated metabolite dextrorphan was markedly increased (p<0.001). Furthermore, there was demonstrated a highly significant stimulation of CYP2C6 (p<0.001) in the isolated perfused liver when tolbutamid was used as a selective substrate. On the other hand, the experiments in the isolated liver did not confirm the stimulatory effect of MET on CYP3A subfamily as it could be suggested on the base of the in vivo pharmacokinetic experiments. the study performed in the liver microsomes supplied the detailed view about the direct effects of the in vivo pretreatment of rats with MET on the specific microsomal enzymes. Out of the monooxygenases tested, i.e. ethylresorufin-O-deethylase (EROD, CYP1A1/2), pentylresorufin-O-deethylase (PROD, CYP2B), ethoxycoumarin-O-deethylase (ECOD, CYP2A), erythromycine-N-demethylase (ERDM, CYP3A), 4-nitrophenol hydroxylase (NPH, CYP2E1) and dextromethorphan-O-demethylase (DXDM, CYP2D6), only CYP2D showed an insignificant stimulation and CYP2E1 was markedly inhibited. |
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