Gepirone and 1-(2-pyrimidinyl)-piperazine in vitro : human cytochromes mediating transformation and cytochrome inhibitory effects

• Published in: Psychopharmacologia 1998-12, Vol.140 (3), p.293-299
• Main Authors: VON MOLTKE, L. L, GREENBLATT, D. J, GRASSI, J. M, GRANDA, B. W, FOGELMAN, S. M, HARMATZ, J. S, KRAMER, S. J, FABRE, L. F, SHADER, R. I
• Format: Article
• Language: English
• Subjects: Antidepressive Agents - pharmacokinetics; Biological and medical sciences; Biotransformation; Biotransformation - drug effects; Buspirone - analogs & derivatives; Buspirone - metabolism; Cytochrome; Cytochrome P-450 Enzyme System - metabolism; Cytochromes; Drug Interactions; Drug metabolism; Hepatocytes; Humans; Ketoconazole; Ketoconazole - pharmacology; Liver; Medical sciences; Metabolites; Microsomes; Microsomes, Liver - metabolism; Neuropharmacology; Pharmacology. Drug treatments; Piperazine; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Pyrimidines - pharmacokinetics; Quinidine
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s002130050770

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 Km ranging from 335 to 677 microM. Coincubation with 1 microM ketoconazole reduced reaction velocity to less than 5% of control values at a gepirone concentration of 250 microM. 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 microM ketoconazole; quinidine at 1 microM 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 Km of 849 microM; Km values for the other metabolites were 245, 240, and 415 microM. 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 activity 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.