Bickel M, Baader E, Brocks D G, Engelbart K, Günzler V, Schmidts H L, Vogel G H
Hoechst, AG, Pharma Research, Frankfurt, Federal Republic of Germany.
J Hepatol. 1991;13 Suppl 3:S26-33; discussion S34. doi: 10.1016/0168-8278(91)90005-v.
S 0885 and HOE 077 inhibit CCl4-induced liver fibrosis in rats, as shown by significantly reduced hydroxyproline content of the liver and improved liver histology. Mortality of drug-treated animals is significantly diminished. Serum collagen parameters correlate well with the hydroxyproline content of the liver and can be used as noninvasive markers for the fibrotic process. HOE 077 is a proinhibitor, which by itself does not inhibit prolyl 4-hydroxylase. HOE 077 is well absorbed from the gastrointestinal tract. It is taken up by rat liver and is converted to the active metabolites. At a concentration of 1 mM, HOE 077 does not affect collagen synthesis in human fibroblasts, bovine chondrocytes and chicken calvaria. At therapeutic doses the compound does not reduce collagen content of kidney, lung, aorta, femur epiphysis, skin and tendon of the rat, validating the high specifity of the liver selective prodrug/inhibitor conversion. From animal experiments, a human daily dose of 0.5-1 g can be extrapolated.
S 0885和HOE 077可抑制大鼠四氯化碳诱导的肝纤维化，表现为肝脏羟脯氨酸含量显著降低，肝脏组织学改善。药物治疗动物的死亡率显著降低。血清胶原蛋白参数与肝脏羟脯氨酸含量密切相关，可作为纤维化过程的非侵入性标志物。HOE 077是一种前体抑制剂，其本身并不抑制脯氨酰4-羟化酶。HOE 077可从胃肠道很好地吸收。它被大鼠肝脏摄取并转化为活性代谢物。在1 mM的浓度下，HOE 077不影响人成纤维细胞、牛软骨细胞和鸡颅骨的胶原蛋白合成。在治疗剂量下，该化合物不会降低大鼠肾脏、肺、主动脉、股骨骨骺、皮肤和肌腱的胶原蛋白含量，证实了肝选择性前药/抑制剂转化的高特异性。从动物实验中，可以推断出人类每日剂量为0.5 - 1 g。
