安倍生坦;BSF 208075;LU 208075-abs813296

一、产品概述

二、产品信息

Ambrisentan only increases intracellular calcein fluorescence in P388/dx cells at concentrations above 100 μM and in L-MDR1 cells not at all indicating negligible P-gp inhibition. Ambrisentan inhibits specific ET-1 binding in these tissues in a concentration-dependent manner. Ambrisentan undergoes oxidative metabolism mainly by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP3A5 and CYP2C19. Ambrisentan is not only a strong inducer of CYP3A4, but also of ABCB1 and ABCG2. Ambrisentan also has a concentration-dependent effect on PXR activity, but because plateau effects are not reached, an EC50-value could not be calculated. Ambrisentan inhibits specific ET-1 binding in a concentration-dependent manner at nanomolar ranges of IC50. Ambrisentan significantly increases the dissociation constant for bladder ET-1 binding without affecting maximal number of binding sites (Bmax). Ambrisentan seem to bind to bladder ET-1 receptor in a competitive and reversible manner. Ambrisentan is an effective and safe treatment which is a valuable addition to the armamentarium against PAH. Ambrisentan offers a relative lack of drug interactions, once daily dosing and reassuring liver safety, offering safety and convenience advantages over bosentan.

In the Ambrisentan group, hepatic hydroxyproline content is significantly lower than in the control group (18.0 μg/g±6.1 μg/g vs 33.9 μg/g±13.5 μg/g liver, respectively, P=0.014). Hepatic fibrosis estimated by Sirius red staining and areas positive for α-smooth muscle actin, indicative of activated hepatic stellate cells, are also significantly lower in the Ambrisentan group (0.46%±0.18% vs 1.11%±0.28%, respectively, P=0.0003; and 0.12%±0.08% vs 0.25%±0.11%, respectively, P=0.047). Moreover, hepatic RNA expression levels of procollagen-1 and tissue inhibitor of metalloproteinase-1 (TIMP-1) are significantly lower by 60% and 45%, respectively, in the Ambrisentan group. Inflammation, steatosis, and endothelin-related mRNA expression in the liver are not significantly different between the groups. Ambrisentan attenuates the progression of hepatic fibrosis by inhibiting hepatic stellate cell activation and reducing procollagen-1 and TIMP-1 gene expression. Ambrisentan did not affect inflammation or steatosis.

三、背景

四、制备和贮存

五、产品特点

六、注意事项