title: Gepirone and 1-(2-pyrimidinyl)-piperazine in vitro: human cytochromes mediating transformation and cytochrome inhibitory effects.
abstract: 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.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: L L
authors.initials: LL
authors.lastname: von Moltke
authors.forename: D J
authors.initials: DJ
authors.lastname: Greenblatt
authors.forename: J M
authors.initials: JM
authors.lastname: Grassi
authors.forename: B W
authors.initials: BW
authors.lastname: Granda
authors.forename: S M
authors.initials: SM
authors.lastname: Fogelman
authors.forename: J S
authors.initials: JS
authors.lastname: Harmatz
authors.forename: S J
authors.initials: SJ
authors.lastname: Kramer
authors.forename: L F
authors.initials: LF
authors.lastname: Fabre
authors.forename: R I
authors.initials: RI
authors.lastname: Shader
mesh_terms: D000928:Antidepressive Agents / Q000493:pharmacokinetics*; D001711:Biotransformation / Q000187:drug effects; D002065:Buspirone / Q000031:analogs & derivatives* / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism; D011743:Pyrimidines / Q000493:pharmacokinetics*
chemical_list: D000928:Antidepressive Agents; D011743:Pyrimidines; D003577:Cytochrome P-450 Enzyme System; C037921:1-(2-pyrimidinyl)piperazine; C039979:gepirone; D007654:Ketoconazole; D002065:Buspirone