Influence of 5-HT1 receptor agonists on the activity of CYP2D1 and N-acetyltransferase in the isolated perfused rat liver
| Authors | |
|---|---|
| Year of publication | 2001 |
| Type | Article in Periodical |
| Magazine / Source | Homeostasis |
| MU Faculty or unit | |
| Citation | |
| Field | Pharmacology and pharmaceutical chemistry |
| Description | The study was aimed to determine if the pretreatment with the selected 5-HT1 receptor agonists, CGS 12066B (5-HT1B), RU-24969 (5-HT1A/B and sumatriptan (5-HT1B/D), may affect oxidative and/or conjugative drug metabolism in the isolated perfused rat liver. Cytochrome P450 2D1-mediated O-demethylation of dextromethorphan (DEM)to dextrorphan (DOR), and arylamine N-acetyltransferase (NAT2)-mediated N-acetylation of procainamide (PA) to N-acetylprocainamide (NAPA), were used as representative, clinically important, metabolic reactions. The results showed a significant decrease in O-demethylation of DEM to DOR in all measured intervals (30 - 60 - 120 min) of the liver perfusion after the pretreatment with selective 5-HT1B agonist CGS 12066B and 5-HT1A/B agonist RU-24969. Sumatriptan however had no substantial effect on the CYP2D1 O-demethylation activity. The effect of 5-HT1 agonists on the N-acetylation of procainamide (substrate for NAT2), was much less marked; CGS 12066B and sumatriptan produced a significant inhibition of the arylamine N-acetyltransferase activity only in the late (120 min) phase of the liver perfusion, RU-24969 had no effect detected. Thus current results indicate that selective ligands of serotonin receptors subtypes show less expressed adverse effects than previously used non-selective drugs, and their pharmacokinetic profiles should be considered as important factors for their therapeutic use. The lack of metabolic interference of sumatriptan may be favourable in the combined therapy of migraine. In contrast, the inhibitory effect of CGS 12066B and RU-24969 on the liver CYP2D1 activity represents an impact feature in case of their introduction into the therapy. |
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