Gepirone and 1-(2-pyrimidinyl)-piperazine in vitro: human cytochromes mediating transformation and cytochrome inhibitory effects
| Autor: | Richard I. Shader, Jerold S. Harmatz, David J. Greenblatt, Jeffrey M. Grassi, L L von Moltke, L. F. Fabre, Steven M. Fogelman, Brian W. Granda, S. J. Kramer |
|---|---|
| Rok vydání: | 1998 |
| Předmět: |
Cytochrome
Stereochemistry Metabolite chemistry.chemical_compound Gepirone Cytochrome P-450 Enzyme System medicine Humans Drug Interactions Biotransformation Pharmacology biology Cytochrome P450 Metabolism Antidepressive Agents Buspirone Ketoconazole Pyrimidines Biochemistry chemistry Microsomes Liver biology.protein Microsome Drug metabolism medicine.drug |
| Zdroj: | Psychopharmacology. 140:293-299 |
| ISSN: | 1432-2072 0033-3158 |
| DOI: | 10.1007/s002130050770 |
| Popis: | Biotransformation of gepirone to its principal metabolite, 1-(2-pyrimidinyl)-piperazine (1-PP), was studied in human liver microsomes and in microsomes from cDNA-transfected human lymphoblastoid cells. Formation of 1-PP from gepirone in liver microsomes proceeded with a mean apparent K m ranging from 335 to 677 μM. Coincubation with 1 μM ketoconazole reduced reaction velocity to less than 5% of control values at a gepirone concentration of 250 μM. Three other metabolites, presumed to be hydroxylated products, were also formed from gepirone. Formation of all three products was reduced to approximately 20% of control values by 1 μM ketoconazole; quinidine at 1 μM produced a small reduction in formation (91–94% of control) of two of the metabolites. 1-PP was formed from gepirone exclusively by pure P450-3A4 with a K m of 849 μM; K m values for the other metabolites were 245, 240, and 415 μM. Two of the products were also formed by P450-2D6. The results indicate that 3A4 is the principal cytochrome mediating 1-PP formation, as well as formation of the other metabolites. The properties of gepirone and 1-PP themselves as cytochrome inhibitors were tested in human liver microsomes using index reactions representing activitiy of P450-1A2, -2C9, -2C19, -2D6, -2E1 and -3A. Gepirone and 1-PP produced negligible inhibition of all these reactions. Thus gepirone at therapeutic doses in humans has a low likelihood of inhibiting P450-mediated drug metabolism involving these cytochromes. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|