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

Biotransformation of gepirone to its principal metabolite, 1-(2-pyrimidinyl )-piperazine (1-PP), was studied in human liver microsomes and in microsome s from cDNA-transfected human lymphoblastoid cells. Formation of 1-PP from gepirone in liver microsomes proceeded with a mean apparent K-m ranging fro m 335 to 677 mu M. Coincubation with 1 mu M ketoconazole reduced reaction v elocity to less than 5% of control values at a gepirone concentration of 25 0 mu M Three other metabolites, presumed to be hydroxylated products, were also formed from gepirone. Formation of all three products was reduced to a pproximately 20% of control values by 1 mu M ketoconazole; quinidine at 1 m u M produced a small reduction in formation (91-94% of control) of two of t he metabolites. 1-PP was formed from gepirone exclusively by pure P450-3A4 with a K-m of 849 mu M; K-m values for the other metabolites were 245, 240, and 415 mu M. Two of the products were also formed by P450-2D6. The result s indicate that 3A4 is the principal cytochrome mediating 1-PP formation, a s well as formation of the other metabolites. The properties of gepirone an d 1-PP themselves as cytochrome inhibitors were tested in human liver micro somes using index reactions representing activitiy of P450-1A2, -2C9, -2C19 , -2D6, -2E1 and -3A. Gepirone and 1-PP produced negligible inhibition of a ll these reactions. Thus gepirone at therapeutic doses in humans has a low likelihood of inhibiting P450-mediated drug metabolism involving these cyto chromes.