Kitamura Atsushi, Mizuno Yoshiko, Natsui Kiyoshi, Yabuki Masashi, Komuro Setsuko, Kanamaru Hiroshi
Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd, 1-98 Kasugade-naka 3-chome, Konohana-ku, Osaka 554-8588, Japan.
Biopharm Drug Dispos. 2005 Mar;26(2):59-65. doi: 10.1002/bdd.432.
In vitro studies were carried out to identify the major contribution of CYP2C8, CYP2D6 and CYP3A4 to the metabolism of perospirone (cis-N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]cyclohexane-1,2-dicarboximide monohydrochloride dehydrate), a novel antipsychotic agent, using human liver microsomes and expressed P450 isoforms. Quinidine (a specific inhibitor of CYP2D6) did not markedly affect the metabolism of perospirone, whereas quercetin (an inhibitor of CYP2C8) and ketoconazole (an inhibitor of CYP3A4) caused a decrease in the metabolism with human liver microsomes in a concentration dependent fashion. With 10 microM quercetin, the metabolism of perospirone was inhibited by 60.0% and with 1 microM ketoconazole almost complete inhibition was apparent. Anti-CYP2C8 and anti-CYP2D6 antisera did not exert marked effects, whereas anti-CYP3A4 antiserum caused almost complete inhibition. With expressed P450s, K(m) and V(max) values were 1.09 microM and 1.93 pmol/min/pmol P450 for CYP2C8, 1.38 microM and 5.73 pmol/min/pmol P450 for CYP2D6, and 0.245 microM and 61.3 pmol/min/pmol P450 for CYP3A4, respectively. These results indicated that the metabolism of perospirone in human liver was mainly catalysed by CYP3A4, and to a lesser extent CYP2C8 and CYP2D6 were responsible because kinetic data (K(m) and V(max)) of CYP2C8 and CYP2D6 suggested catalytic potential.
进行了体外研究，以确定细胞色素P450 2C8（CYP2C8）、细胞色素P450 2D6（CYP2D6）和细胞色素P450 3A4（CYP3A4）对新型抗精神病药物哌罗匹隆（顺式-N-[4-[4-(1,2-苯并异噻唑-3-基)-1-哌嗪基]丁基]环己烷-1,2-二甲酰亚胺盐酸盐脱水物）代谢的主要贡献，采用人肝微粒体和表达的P450同工酶。奎尼丁（CYP2D6的特异性抑制剂）对哌罗匹隆的代谢没有明显影响，而槲皮素（CYP2C8的抑制剂）和酮康唑（CYP3A4的抑制剂）与人肝微粒体共同作用时，会使代谢呈浓度依赖性降低。使用10微摩尔槲皮素时，哌罗匹隆的代谢被抑制60.0%，使用1微摩尔酮康唑时几乎完全抑制。抗CYP2C8和抗CYP2D6抗血清没有显著作用，而抗CYP3A4抗血清几乎完全抑制了代谢。对于表达的P450，CYP2C8的米氏常数（K(m)）和最大反应速度（V(max)）值分别为1.09微摩尔和1.93皮摩尔/分钟/皮摩尔P450，CYP2D6的分别为1.38微摩尔和5.73皮摩尔/分钟/皮摩尔P450，CYP3A4的分别为0.245微摩尔和61.3皮摩尔/分钟/皮摩尔P450。这些结果表明，人肝中哌罗匹隆的代谢主要由CYP3A4催化，CYP2C8和CYP2D6在较小程度上也有作用，因为CYP2C8和CYP2D6的动力学数据（K(m)和V(max)）显示了催化潜力。
