Pasha Mohammed Khalid, Jayaraman Ramesh, Reddy Venkatesh Pilla, Yeo Pauline, Goh Evelyn, Williams Anthony, Goh Kee Chuan, Kantharaj Ethirajulu
S*BIO Pte Ltd, 1 Science Park Road, No. 05-09, The Capricorn, Singapore Science Park II, Singapore.
Drug Metab Lett. 2012 Mar;6(1):33-42. doi: 10.2174/187231212800229336.
SB1317 (TG02) is a novel small molecule potent CDK/JAK2/FLT3 inhibitor. To evaluate full potential of this development candidate, we conducted drug metabolism and pharmacokinetic studies of this novel anti-cancer agent. SB1317 was soluble, highly permeable in Caco-2 cells, and showed > 99% binding to plasma from mice, dog and humans. It was metabolically stable in human and dog liver microsomes relative to mouse and rat. SB1317 was mainly metabolized by CYP3A4 and CY1A2 in vitro. SB1317 did not inhibit any of the major human CYPs in vitro except CYP2D6 (IC50=1 μM). SB1317 did not significantly induce CYP1A and CYP3A4 in human hepatocytes in vitro. The metabolic profiles in liver microsomes from preclinical species were qualitatively similar to humans. In pharmacokinetic studies SB1317 showed moderate to high systemic clearance (relative to liver blood flow), high volume of distribution ( > 0.6 L/kg), oral bioavailability of 24%, ∼ 4 and 37% in mice, rats and dogs, respectively; and extensive tissue distribution in mice. The favorable ADME of SB1317 supported its preclinical development as an oral drug candidate.
SB1317（TG02）是一种新型小分子强效CDK/JAK2/FLT3抑制剂。为评估这一开发候选药物的全部潜力，我们对这种新型抗癌药物进行了药物代谢和药代动力学研究。SB1317可溶，在Caco-2细胞中具有高渗透性，并且与小鼠、犬和人类的血浆结合率>99%。相对于小鼠和大鼠，它在人和犬肝微粒体中代谢稳定。SB1317在体外主要由CYP3A4和CY1A2代谢。SB1317在体外除了对CYP2D6（IC50 = 1 μM）外，不抑制任何主要的人细胞色素P450酶。SB1317在体外人肝细胞中不显著诱导CYP1A和CYP3A4。临床前物种肝微粒体中的代谢谱在质量上与人类相似。在药代动力学研究中，SB1317显示出中度至高的全身清除率（相对于肝血流量）、高分布容积（>0.6 L/kg），在小鼠、大鼠和犬中的口服生物利用度分别为24%、约4%和37%；并且在小鼠中具有广泛的组织分布。SB1317良好的吸收、分布、代谢和排泄特性支持其作为口服药物候选物的临床前开发。
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