characterization of in vitro and in vivo metabolism of ag-024322, a novel cyclin-dependent kinase (cdk)描述体外和体内代谢的ag - 024322,一种新的细胞周期蛋白依赖性激酶(cdk).pdfVIP

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characterization of in vitro and in vivo metabolism of ag-024322, a novel cyclin-dependent kinase (cdk)描述体外和体内代谢的ag - 024322,一种新的细胞周期蛋白依赖性激酶(cdk).pdf

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characterization of in vitro and in vivo metabolism of ag-024322, a novel cyclin-dependent kinase (cdk)描述体外和体内代谢的ag - 024322,一种新的细胞周期蛋白依赖性激酶(cdk)

Vol.1, No.4, 249-262 (2009) Health doi:10.4236/health.2009.14041 Characterization of in vitro and in vivo metabolism of AG-024322, a novel cyclin-dependent kinase (CDK) inhibitor * 1 2 Wei-Zhu Zhong , Bojan Lalovic , Jenny Zhan 1Clinical Pharmacology, Pfizer Global Research and Development, New London, Connecticut, USA 2Metabolism and Pharmacokinetics, Novartis Institute of Biomedical Research, Cambridge, Massachusetts, USA * Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, San Diego, California, USA; wei-zhu.zhong@ Received 16 November 2009; revised 25 November 2009; accepted 28 November 2009. ABSTRACT the first human study, thereby decreasing the potential risk of toxicity to patients. Uncontrolled cell proliferation is the hall mark of many cancers, and is typically manifested by a Keywords: Microsomes; Hepatocytes; Reaction deregulation of the cell-division cycle. CDKs Phenotyping; Metabolite Formation Kinetics; play critical roles in regulating cell cycle, apop- CYP3A4; UGT1A1; Mass Balance in Rat tosis and cell differentiation. AG-024322 is a multitargeted CDK inhibitor that has been shown to induce cancer cell apoptosis and de- 1. INTRODUCTION monstrate significant antitumor activity in hu- man tumor xenograft models. This compound is AG-024322, N-({5-[3-(4,6-difluoro-1H-benzimidazol-2- under clinical development as an intravenous