阿托伐他汀ADME
中文名称
通路描述
阿托伐他汀（ATV，商品名立普妥），是一种他汀类降脂药物。它抑制肝脏内胆固醇的内源性合成，从而降低异常高水平的胆固醇和脂质水平，最终降低心血管疾病风险。他汀类药物抑制羟甲基戊二酸单酰辅酶A还原酶（HMGCR），该酶催化胆固醇生物合成中的关键步骤，即HMG-CoA转化为甲戊二酸。他汀类药物是治疗异常脂质水平最常用的处方药（Malhotra & Goa 2001）。ATV及其羟基代谢物共同抑制HMGCR以减少循环低密度脂蛋白胆固醇。ATV几乎完全以血浆蛋白结合形式（>98%）运输于血液中（Lennernas 2003），并受胃肠道前体系统清除和首过肝清除的影响，这解释了其低系统性生物利用度（约12%）（Garcia et al. 2003）。有机阴离子转运体OATP1B1、OATP1B3和OATP2B1，分别由SLCO1B1、SLCO1B3和SLCO2B1编码，表达于肝细胞窦状膜上，并可以促进ATV等药物的肝脏摄取（Kalliokoski & Niemi 2009）。在肝细胞（以及胃肠道中较少见）中，ATV可由细胞色素P450 3A4（CYP3A4）羟基化生成羟基代谢物，或通过不稳定的酰基葡糖苷中间体经UGT1A3和1A1介导的酯化反应生成ATVL。ATVL也可由CYP3A4羟基化生成羟基酮代谢物。酮代谢物对HMGCR无活性，但可通过胰蛋白酶原酶（PONs）水解为相应的羟基酸，后者对HMGCR有活性。ATV及其代谢物的消除主要经胆汁排泄，似乎没有显著的肠肝循环。半衰期（t1/2）约为14小时（阿托伐他汀）和20-30小时（其代谢物）（Schachter 2005）。
英文描述
Atorvastatin ADME Atorvastatin (ATV, brand name Lipitor), is a lipid-lowering drug of the statin class of medications. It inhibits the endogenous production of cholesterol in the liver, thereby lowering abnormally high cholesterol and lipid levels, and ultimately reducing the risk of cardiovascular disease. Statins inhibit the enzyme hydroxymethylglutaryl-coenzyme A reductase (HMGCR) , which catalyzes the critical step in cholesterol biosynthesis of HMG-CoA conversion to mevalonic acid. Statins are the most commonly prescribed medication for treating abnormal lipid levels (Malhotra & Goa 2001). ATV and its hydroxy-metabolites collectively inhibit HMGCR to reduce circulating low-density lipoprotein cholesterol.
ATV is transported in the blood almost exclusively bound to plasma proteins (>98%) (Lennernas 2003), and is subject to preâsystemic clearance at the gastrointestinal tract and to firstâpass hepatic clearance, which explains its low systemic bioavailability (~12%) (Garcia et al. 2003). Organic anion transporters OATP1B1, OATP1B3 and OATP2B1, encoded by SLCO1B1, SLCO1B3, and SLCO2B1, respectively are expressed on the sinusoidal membrane of hepatocytes and can facilitate the liver uptake of drugs such as ATV (Kalliokoski & Niemi 2009).
In hepatocytes (and to a lesser extent, the GI tract), ATV can be hydroxylated by cytochrome P450 3A4 (CYP3A4) to hydroxy-metabolites, or undergo lactonization via an unstable acyl glucuronide intermediate to ATV lactone (ATVL) mediated by UGT1A3 and 1A1. ATVL may also be hydroxylated by CYP3A4 to hydroxylactone-metabolites. The lactone metabolites are inactive against HMGCR, but can be hydrolyzed via paraoxonases (PONs) to their corresponding hydroxy acids, which are active against HMGCR. Elimination of ATV and its metabolites is principally biliary with apparently no significant enterohepatic recirculation. Half-life (t1/2) is approximately 14 h for atorvastatin and 20â30 h for its metabolites (Schachter 2005).
ATV is transported in the blood almost exclusively bound to plasma proteins (>98%) (Lennernas 2003), and is subject to preâsystemic clearance at the gastrointestinal tract and to firstâpass hepatic clearance, which explains its low systemic bioavailability (~12%) (Garcia et al. 2003). Organic anion transporters OATP1B1, OATP1B3 and OATP2B1, encoded by SLCO1B1, SLCO1B3, and SLCO2B1, respectively are expressed on the sinusoidal membrane of hepatocytes and can facilitate the liver uptake of drugs such as ATV (Kalliokoski & Niemi 2009).
In hepatocytes (and to a lesser extent, the GI tract), ATV can be hydroxylated by cytochrome P450 3A4 (CYP3A4) to hydroxy-metabolites, or undergo lactonization via an unstable acyl glucuronide intermediate to ATV lactone (ATVL) mediated by UGT1A3 and 1A1. ATVL may also be hydroxylated by CYP3A4 to hydroxylactone-metabolites. The lactone metabolites are inactive against HMGCR, but can be hydrolyzed via paraoxonases (PONs) to their corresponding hydroxy acids, which are active against HMGCR. Elimination of ATV and its metabolites is principally biliary with apparently no significant enterohepatic recirculation. Half-life (t1/2) is approximately 14 h for atorvastatin and 20â30 h for its metabolites (Schachter 2005).
所含基因
8 个基因