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
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA.
Psychopharmacology (Berl). 1998 Dec;140(3):293-9. 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.
在人肝微粒体以及来自经cDNA转染的人淋巴母细胞的微粒体中，研究了吉哌隆向其主要代谢产物1-(2-嘧啶基)-哌嗪（1-PP）的生物转化。在肝微粒体中，吉哌隆生成1-PP的平均表观Km范围为335至677微摩尔。在吉哌隆浓度为250微摩尔时，与1微摩尔酮康唑共同孵育可使反应速度降至对照值的5%以下。吉哌隆还生成了另外三种代谢产物，推测为羟基化产物。1微摩尔酮康唑使所有这三种产物的生成量降至对照值的约20%；1微摩尔奎尼丁使其中两种代谢产物的生成量略有降低（为对照值的91 - 94%）。吉哌隆仅通过纯P450 - 3A4生成1-PP，其Km为849微摩尔；其他代谢产物的Km值分别为245、240和415微摩尔。其中两种产物也由P450 - 2D6生成。结果表明，3A4是介导1-PP以及其他代谢产物生成的主要细胞色素。使用代表P450 - 1A2、-2C9、-2C19、-2D6、-2E1和-3A活性的指示反应，在人肝微粒体中测试了吉哌隆和1-PP自身作为细胞色素抑制剂的特性。吉哌隆和1-PP对所有这些反应的抑制作用可忽略不计。因此，在人类治疗剂量下，吉哌隆抑制涉及这些细胞色素的P450介导的药物代谢的可能性较低。
