Kamel Amin, Colizza Kevin, Gunduz Mithat, Harriman Shawn, Obach R Scott
Department of Pharmacokinetics, Pharmacodynamics and Metabolism, Pfizer Global Research and Development, Groton/New London Laboratories, Pfizer Inc., Groton, CT, USA.
Xenobiotica. 2012 Apr;42(4):355-62. doi: 10.3109/00498254.2011.630490. Epub 2011 Nov 22.
Oxidative deamination of the GABA(A) partial agonist CP-409,092 and sumatriptan represents a major metabolic pathway and seems to play an important role for the clearance of these two compounds. Similar to sumatriptan, human mitochondrial incubations with deprenyl and clorgyline, probe inhibitors of monoamine oxidase B and monoamine oxidase A (MAO-B and MAO-A), respectively, showed that CP-409,092 was metabolized to a large extent by the enzyme MAO-A. The metabolism of CP-409,092 and sumatriptan was therefore studied in human liver mitochondria and in vitro intrinsic clearance (CL(int)) values were determined and compared to the corresponding in vivo oral clearance (CL(PO)) values. The overall objective was to determine whether an in vitro-in vivo correlation (IVIVC) could be described for compounds cleared by MAO-A. The intrinsic clearance, CL(int), of CP-409,092 was approximately 4-fold greater than that of sumatriptan (CL(int), values were calculated as 0.008 and 0.002 ml/mg/min for CP-409,092 and sumatriptan, respectively). A similar correlation was observed from the in vivo metabolic data where the unbound oral clearance, CL(u)(PO), values in humans were calculated as 724 and 178 ml/min/kg for CP-409,092 and sumatriptan, respectively. The present work demonstrates that it is possible to predict in vivo metabolic clearance from in vitro metabolic data for drugs metabolized by the enzyme monoamine oxidase.
γ-氨基丁酸A型（GABA(A)）部分激动剂CP - 409,092和舒马曲坦的氧化脱氨作用是主要的代谢途径，似乎对这两种化合物的清除起着重要作用。与舒马曲坦相似，分别用单胺氧化酶B和单胺氧化酶A（MAO - B和MAO - A）的探针抑制剂司来吉兰和氯吉兰对人线粒体进行孵育，结果显示CP - 409,092在很大程度上被MAO - A酶代谢。因此，对CP - 409,092和舒马曲坦在人肝线粒体中的代谢进行了研究，并测定了体外内在清除率（CL(int)）值，并与相应的体内口服清除率（CL(PO)）值进行比较。总体目标是确定对于由MAO - A清除的化合物是否可以描述体外-体内相关性（IVIVC）。CP - 409,092的内在清除率CL(int)大约是舒马曲坦的4倍（CP - 409,092和舒马曲坦的CL(int)值分别计算为0.008和0.002 ml/mg/min）。从体内代谢数据中观察到类似的相关性，其中人未结合口服清除率CL(u)(PO)值对于CP - 409,092和舒马曲坦分别计算为724和178 ml/min/kg。目前的工作表明，对于由单胺氧化酶代谢的药物，有可能从体外代谢数据预测体内代谢清除率。
