Caldwell J
Department of Pharmacology and Toxicology, St. Mary's Hospital Medical School, London, UK.
Cardiology. 1989;76 Suppl 1:33-41; discussion 41-4. doi: 10.1159/000174545.
Fenofibrate is metabolized in several stages. First, the carboxyl ester moiety is cleaved by hydrolysis, resulting in fenofibric acid, the main pharmacologically active compound. Fenofibric acid, in turn, undergoes carbonyl reduction, resulting in a pharmacologically active metabolite referred to as reduced fenofibric acid. Both fenofibric acid and reduced fenofibric acid may be conjugated to form glucuronides. There are important species differences in the metabolism and elimination patterns of fenofibrate. In the rat and dog, fenofibric acid and reduced fenofibric acid are the principal metabolites. In humans, the glucuronide of fenofibric acid is predominant. In the rat and dog, approximately 70-80% of fenofibrate and its metabolites are recovered in the feces, whereas in humans approximately 65% of the dose is excreted in the urine. Several mechanisms contribute to fenofibrate's hypolipidemic action, including inhibition of fatty acid synthesis, stimulation of fatty acid beta-oxidation, inhibition of triglyceride synthesis, and enhancement of lipoprotein lipase activity. Fenofibrate's hypocholesterolemic action is a result of both decreased biosynthesis of cholesterol through inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and increased low-density lipoprotein (LDL) clearance via modulation of hepatic LDL receptors. Fenofibrate also has three other actions that may result in the prevention or at least slowing of atherogenesis, namely inhibition of cholesterol esterification, platelet aggregation, and platelet-derived growth factor. The native acyl glucuronide of fenofibric acid is very stable, and is unlikely to have any toxic potential. Although the elimination half-life of fenofibrate is prolonged in the elderly and in patients with impaired hepatic function, the area under the curve and its clearance are not altered because of compensatory changes in the volume of distribution.
非诺贝特在几个阶段进行代谢。首先，羧基酯部分通过水解被裂解，产生非诺贝酸，即主要的药理活性化合物。非诺贝酸继而进行羰基还原，产生一种被称为还原型非诺贝酸的药理活性代谢物。非诺贝酸和还原型非诺贝酸均可结合形成葡糖醛酸苷。非诺贝特的代谢和消除模式存在重要的种属差异。在大鼠和狗中，非诺贝酸和还原型非诺贝酸是主要代谢物。在人类中，非诺贝酸的葡糖醛酸苷占主导。在大鼠和狗中，约70 - 80%的非诺贝特及其代谢物在粪便中回收，而在人类中，约65%的剂量经尿液排泄。几种机制促成了非诺贝特的降血脂作用，包括抑制脂肪酸合成、刺激脂肪酸β -氧化、抑制甘油三酯合成以及增强脂蛋白脂肪酶活性。非诺贝特的降胆固醇作用是通过抑制3 -羟基 - 3 -甲基戊二酰辅酶A还原酶活性减少胆固醇生物合成以及通过调节肝低密度脂蛋白（LDL）受体增加低密度脂蛋白清除率的结果。非诺贝特还有其他三种可能导致预防或至少减缓动脉粥样硬化形成的作用，即抑制胆固醇酯化、血小板聚集和血小板衍生生长因子。非诺贝酸的天然酰基葡糖醛酸苷非常稳定，不太可能具有任何潜在毒性。尽管非诺贝特在老年人和肝功能受损患者中的消除半衰期延长，但由于分布容积的代偿性变化，曲线下面积及其清除率并未改变。
