Abernethy D R, Schwartz J B
Division of Clinical Pharmacology, Brown University, Providence, Rhode Island.
Clin Pharmacokinet. 1988 Jul;15(1):1-14. doi: 10.2165/00003088-198815010-00001.
Calcium antagonist drugs under clinical development are of the Type I (verapamil, diltiazem-like) and Type II (nifedipine-like) classes. Tiapamil, the only Type I drug currently available, is a high clearance, widely distributed drug which undergoes extensive presystemic elimination. Pharmacokinetically it is quite similar to verapamil; however, it does have increased biliary excretion and decreased binding to plasma proteins. Eight Type II (dihydropyridine) drugs are reviewed. Seven of these drugs (felodipine, isradipine, nicardipine, nilvadipine, nimodipine, nisoldipine and nitrendipine) are pharmacokinetically similar to nifedipine, with high clearance, extensive distribution, and significant presystemic elimination. Amlodipine has lower clearance, even greater peripheral distribution, and greatly decreased presystemic elimination. Three of the 8 dihydropyridines have been reported to have plasma protein binding greater than 90%. Unlike nifedipine, each dihydropyridine drug under development has an asymmetric centre; therefore each in fact is a racemic mixture. Human pharmacokinetic and pharmacodynamic data have not been reported for any of the racemates. Each of the drugs has been studied in patients with hepatic and renal disease. Predictably, patients with severe hepatic disease have decreased presystemic clearance and, in some cases decreased clearance after intravenous administration of the dihydropyridines, although renal failure has little influence on their pharmacokinetics. Unfortunately, disease-drug interaction studies of this class of drugs do not generally report plasma protein binding. The effect of age on the disposition of 2 of the dihydropyridines has been reported; however, only for nicardipine can a conclusion be drawn, namely that volume of distribution may increase with age and clearance may remain unchanged. A variety of potential drug-drug interactions have been evaluated, most commonly the effect of these drugs on cardiac glycoside disposition and effect, and the effect of cimetidine on the disposition of dihydropyridines. Tiapamil, like verapamil, impairs digoxin clearance significantly. Among the dihydropyridines, although minor pharmacokinetic effects have in some cases been reported, the magnitude of the interactions suggest they have limited clinical importance. From drugs currently under development, it is clear that a large number of calcium antagonists will soon be introduced into clinical use. Only 1 of the newer drugs, amlodipine, has significant pharmacokinetic differences from the agents currently in use, although possible pharmacodynamic differences among the drugs have been suggested.(ABSTRACT TRUNCATED AT 400 WORDS)
正在进行临床开发的钙拮抗剂药物分为I型（维拉帕米、地尔硫䓬类）和II型（硝苯地平类）。目前唯一可用的I型药物替帕米是一种高清除率、广泛分布的药物，存在广泛的首过消除。其药代动力学与维拉帕米非常相似；然而，它的胆汁排泄增加，与血浆蛋白的结合减少。本文综述了8种II型（二氢吡啶类）药物。其中7种药物（非洛地平、伊拉地平、尼卡地平、尼伐地平、尼莫地平、尼索地平、尼群地平）的药代动力学与硝苯地平相似，具有高清除率、广泛分布和显著的首过消除。氨氯地平的清除率较低，外周分布更广，首过消除大大减少。据报道，8种二氢吡啶类药物中有3种的血浆蛋白结合率大于90%。与硝苯地平不同，每种正在开发的二氢吡啶类药物都有一个不对称中心；因此，实际上每种药物都是外消旋混合物。尚未报道任何外消旋体的人体药代动力学和药效学数据。每种药物都在肝病和肾病患者中进行了研究。可以预见，严重肝病患者的首过清除率降低，在某些情况下，静脉注射二氢吡啶类药物后的清除率也会降低，尽管肾衰竭对其药代动力学影响很小。不幸的是，这类药物的疾病-药物相互作用研究通常不报告血浆蛋白结合情况。已经报道了年龄对2种二氢吡啶类药物处置的影响；然而，仅对尼卡地平可以得出结论，即分布容积可能随年龄增加而清除率可能保持不变。已经评估了多种潜在的药物-药物相互作用，最常见的是这些药物对强心苷处置和效应的影响，以及西咪替丁对二氢吡啶类药物处置的影响。替帕米与维拉帕米一样，会显著损害地高辛的清除率。在二氢吡啶类药物中，尽管在某些情况下已报道有轻微的药代动力学效应，但相互作用的程度表明它们的临床重要性有限。从目前正在开发的药物来看，很明显大量的钙拮抗剂很快将被引入临床使用。较新的药物中只有氨氯地平与目前使用的药物有显著的药代动力学差异，尽管已有人提出药物之间可能存在药效学差异。（摘要截取自400字）
