药效学和药物动力学的β-还原酶抑制剂。相似点和不同点。
文章的细节
-
引用
复制到剪贴板 -
Lennernas H,费奇G
药效学和药物动力学的β-还原酶抑制剂。相似点和不同点。
Pharmacokinet。1997年5月,32 (5):403 - 25。doi: 10.2165 / 00003088-199732050-00005。
- PubMed ID
-
9160173 (在PubMed]
- 文摘
-
血胆甾醇过多起着至关重要的作用在动脉粥样硬化疾病的发展、特别是冠心病。动脉粥样硬化过程的进展的风险逐步增加冠心病水平增加的血清总胆固醇和低密度脂蛋白(LDL)胆固醇在个人和人口水平。他汀类药物是可逆的抑制剂的微粒体酶β-还原酶,将β-甲羟戊酸。这是一个早期病原反应一步胆固醇生物合成。β-还原酶的抑制他汀类药物降低细胞内胆固醇生物合成,从而导致转录调节微粒体的生产β-还原酶和细胞表面的低密度脂蛋白受体。随后,还提供了额外的胆固醇从头合成,通过受体介导的细胞吸收血液中的低密度脂蛋白胆固醇。这个重置细胞内胆固醇在肝外组织内稳态,但是几乎没有影响整体胆固醇平衡。没有简单的方法来探讨浓度抑制β-还原酶在人类药效学研究。主要临床变量是血浆低密度脂蛋白胆固醇,它需要4到6周的时间来显示他汀类药物治疗开始后减少。因此,量而不是浓度效应关系是更合适用于描述药效学。 Fluvastatin, lovastatin, pravastatin and simvastatin have similar pharmacodynamic properties; all can reduce LDL-cholesterol by 20 to 35%, a reduction which has been shown to achieve decreases of 30 to 35% in major cardiovascular outcomes. Simvastatin has this effect at doses of about half those of the other 3 statins. The liver is the target organ for the statins, since it is the major site of cholesterol biosynthesis, lipoprotein production and LDL catabolism. However, cholesterol biosynthesis in extrahepatic tissues is necessary for normal cell function. The adverse effects of HMG-reductase inhibitors during long term treatment may depend in part upon the degree to which they act in extrahepatic tissues. Therefore, pharmacokinetic factors such as hepatic extraction and systemic exposure to active compound(s) may be clinically important when comparing the statins. Different degrees of liver selectivity have been claimed for the HMG-CoA reductase inhibitors. However, the literature contains confusing data concerning the degree of liver versus tissue selectivity. Human pharmacokinetic data are poor and incomplete, especially for lovastatin and simvastatin, and it is clear that any conclusion on tissue selectivity is dependent upon the choice of experimental model. However, the drugs do differ in some important aspects concerning the degree of metabolism and the number of active and inactive metabolites. The rather extensive metabolism by different cytochrome P450 isoforms also makes it difficult to characterise these drugs regarding tissue selectivity unless all metabolites are well characterised. The effective elimination half-lives of the hydroxy acid forms of the 4 statins are 0.7 to 3.0 hours. Protein binding is similar (> 90%) for fluvastatin, lovastatin and simvastatin, but it is only 50% for pravastatin. The best characterised statins from a clinical pharmacokinetic standpoint are fluvastatin and pravastatin. The major difference between these 2 compounds is the higher liver extraction of fluvastatin during the absorption phase compared with pravastatin (67 versus 45%, respectively, in the same dose range). Estimates of liver extraction in humans for lovastatin and simvastatin are poorly reported, which makes a direct comparison difficult.