Moghaddam Mehran F, Tang Yang, O'Brien Zhihong, Richardson Samantha J, Bacolod Maria, Chaturedi Prasoon, Apuy Julius, Kulkarni Ashutosh
Department of Drug Metabolism and Pharmacokinetics, Celgene Corporation, 10300 Campus Point Dr, Suite 100, San Diego, CA 92121, USA.
Drug Metab Lett. 2014;8(1):19-30. doi: 10.2174/1872312808666140317151735.
The in vitro and in vivo preclinical ADME properties of 10 clinically late stage or marketed covalent inhibitors were evaluated in order to define advancement criteria for discovery of future drugs in this arena. Our studies revealed the following: After incubating with S9 fractions for 30 minutes, the rat and human in vitro stability for these compounds ranged from 1% to 100%. The blood stability ranged from 30% to 100%. There was a broad range of CYP inhibition with prevalence for time-dependent inhibition of at least one enzyme. The Caco-2 permeability (A→B) ranged from negligible (0.6 x 10(-6) cm/s) to highly permeable (31 x 10(-6) cm/s) and the efflux ratio also varied widely (0.2-30). Most of the compounds were highly protein bound in both rat and human with binding ≥ 90%. Rat plasma clearance for the 10 compounds ranged from slow (11 mL/min/kg) to very rapid (350 mL/min/kg). The Vss ranged from low (0.67 L/kg) to very high (115 L/kg). MRT's also ranged from short (0.5 hr) to long (7.4 hr). The oral exposures also showed a very broad range with CMax's ranging from 0.01-77 μM and exposure levels ranging from 0.03-106 μM.hr. In conclusion, the wide range in in vitro and in vivo ADME data makes these particular ADME assays non-discriminatory in the selection of promising compounds. In our opinion, non-traditional assays such as target mass modification, target confirmation by amino acid sequencing, cellular target occupancy, and target turnover rate data in combination with the pharmacokinetic profiles are the critical considerations for progression of irreversible compounds in early discovery.
为了确定该领域未来药物发现的推进标准，对10种临床晚期或已上市的共价抑制剂的体外和体内临床前药代动力学性质进行了评估。我们的研究结果如下：与S9组分孵育30分钟后，这些化合物在大鼠和人体中的体外稳定性范围为1%至100%。血液稳定性范围为30%至100%。对细胞色素P450酶的抑制作用范围广泛，至少有一种酶存在时间依赖性抑制。Caco-2细胞单层模型的通透系数（A→B）范围从可忽略不计（0.6×10⁻⁶ cm/s）到高通透性（31×10⁻⁶ cm/s），外排率也有很大差异（0.2 - 30）。大多数化合物在大鼠和人体中都有高度的蛋白结合，结合率≥90%。这10种化合物的大鼠血浆清除率范围从缓慢（11 mL/min/kg）到非常快速（350 mL/min/kg）。稳态分布容积范围从低（0.67 L/kg）到非常高（115 L/kg）。平均驻留时间也范围从短（0.5小时）到长（7.4小时）。口服暴露也显示出非常广泛的范围，Cmax范围从0.01 - 77 μM，暴露水平范围从0.03 - 106 μM·hr。总之，体外和体内药代动力学数据的广泛差异使得这些特定的药代动力学分析在筛选有前景的化合物时缺乏区分性。我们认为，在早期发现阶段，非传统分析方法，如靶点质量修饰、通过氨基酸测序进行靶点确认、细胞靶点占有率以及靶点周转率数据结合药代动力学特征，是不可逆化合物进展的关键考虑因素。
