Kates R E
Drugs. 1983 Feb;25(2):113-24. doi: 10.2165/00003495-198325020-00002.
An understanding of the pharmacokinetics of the calcium antagonists (slow-channel blocking drugs) is essential in order to design appropriate dosage regimens which will provide optimum therapeutic efficacy with these agents. This review summarises and evaluates the current state of knowledge of the absorption and disposition characteristics of the 3 most extensively used calcium antagonists in cardiovascular therapeutics: verapamil, diltiazem and nifedipine. While an extensive literature regarding the kinetics of verapamil exists, reports dealing with diltiazem and nifedipine are limited. This is, in part, due to difficulties in developing simple, specific and sensitive analytical procedures. All 3 drugs undergo extensive metabolism in the liver. Metabolites of verapamil (norverapamil) and diltiazem (desacetyldiltiazem) accumulate in the plasma of patients and have been shown to produce some effects similar to those of their parent compounds. The bioavailability of diltiazem and nifedipine has not been well studied, and no investigations of the absolute bioavailability of these compounds have been reported. However, the bioavailability of verapamil has been studied extensively; about 22% of an orally administered dose of verapamil is systemically available. Bioavailability is increased when liver function is impaired, such as in patients with hepatic cirrhosis. The high first-pass extraction of verapamil has been suggested to be stereoselective, with preferential elimination of the (-) isomer. The plasma concentration-time curves of verapamil and diltiazem have been studied following oral administration. The elimination half-lives of verapamil and diltiazem are about 8 and 5 hours, respectively. All 3 drugs are highly protein-bound in the plasma. Several other drugs have the ability to displace verapamil from plasma protein binding sites, but the clinical significance of this interaction is doubtful. Other drug interactions have been investigated with these agents. Verapamil causes digoxin plasma levels to rise during concomitant administration, but no drugs have been shown to alter the disposition of verapamil. Diazepam affects the plasma levels of diltiazem leading to a decrease. The mechanism of this interaction has not been reported, but an effect on bioavailability has been suggested. Age has been shown to be a factor in the disposition of both diltiazem and verapamil. Older patients tend to have lower clearances of these 2 drugs than do younger patients. It has also been shown that hepatic cirrhosis leads to a decreased clearance of verapamil. Plasma level monitoring may be helpful for adjusting doses of both verapamil and diltiazem, despite the absence of a definition of therapeutic plasma concentrations. These agents all have low, and highly variable, systemic availability, and plasma concentrations cannot be predicted after oral administration.
为了设计出能使这些药物发挥最佳治疗效果的合适给药方案，了解钙拮抗剂（慢通道阻滞剂）的药代动力学至关重要。本综述总结并评估了心血管治疗中最广泛使用的3种钙拮抗剂维拉帕米、地尔硫䓬和硝苯地平的吸收及处置特征的当前知识状态。虽然关于维拉帕米动力学的文献很多，但有关地尔硫䓬和硝苯地平的报道有限。这部分是由于难以开发简单、特异且灵敏的分析方法。所有这3种药物在肝脏中都经历广泛代谢。维拉帕米（去甲维拉帕米）和地尔硫䓬（去乙酰地尔硫䓬）的代谢产物在患者血浆中蓄积，并且已显示出产生一些与其母体化合物相似的效应。地尔硫䓬和硝苯地平的生物利用度尚未得到充分研究，也没有关于这些化合物绝对生物利用度的研究报道。然而，维拉帕米的生物利用度已得到广泛研究；口服给药剂量的维拉帕米约22%可被全身利用。当肝功能受损时，如肝硬化患者，生物利用度会增加。维拉帕米的高首过提取被认为具有立体选择性，优先消除（-）异构体。口服给药后研究了维拉帕米和地尔硫䓬的血浆浓度-时间曲线。维拉帕米和地尔硫䓬的消除半衰期分别约为8小时和5小时。所有这3种药物在血浆中都高度与蛋白结合。其他几种药物有能力将维拉帕米从血浆蛋白结合位点上置换下来，但这种相互作用的临床意义尚不确定。已经对这些药物与其他药物的相互作用进行了研究。维拉帕米在同时给药期间会使地高辛血浆水平升高，但尚未显示有药物会改变维拉帕米的处置。地西泮会影响地尔硫䓬的血浆水平，导致其降低。这种相互作用的机制尚未报道，但有人提出是对生物利用度有影响。年龄已被证明是地尔硫䓬和维拉帕米处置的一个因素。老年患者这两种药物的清除率往往比年轻患者低。也已表明肝硬化会导致维拉帕米清除率降低。尽管尚未明确治疗性血浆浓度，但血浆水平监测可能有助于调整维拉帕米和地尔硫䓬的剂量。这些药物的全身利用率都很低且高度可变，口服给药后无法预测血浆浓度。
