THE PHARMACOKINETICS AND PHARMACODYNAMICS OF DILTIAZEM AND ITS METABOLITES IN HEALTHY-ADULTS AFTER A SINGLE ORAL DOSE
THE PHARMACOKINETICS AND PHARMACODYNAMICS OF DILTIAZEM AND ITS METABOLITES IN HEALTHY-ADULTS AFTER A SINGLE ORAL DOSE
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DOI：
10.1038/clpt.1989.159
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发表时间：
1989-10-01
影响因子：
6.7
通讯作者：
GIACOMINI, KM
中科院分区：
文献类型：
--
作者：
BOYD, RA;CHIN, SK;GIACOMINI, KM
口服剂量后地尔硫卓的药代动力学和药效学表征中的一个潜在复杂因素是血浆中存在两种代谢物：N-去甲基地尔硫卓和去乙酰地尔硫卓。 N-去甲基地尔硫卓和去乙酰地尔硫卓均已被证明在动物组织中具有药理活性。因此，这些代谢物可能有助于地尔硫卓的药理作用，但这种可能性尚未得到探索。本研究的目的是研究地尔硫卓、N-去甲基地尔硫卓和去乙酰地尔硫卓的药代动力学和药效学。特别关注地尔硫卓对房室传导的影响。六名健康男性口服 120 毫克地尔硫卓。通过灵敏的 HPLC 方法测量血浆和尿液中地尔硫卓、N-去甲基地尔硫卓和去乙酰地尔硫卓的浓度。在每次采血时测量药理反应（心率、血压和 PR 间期）。地尔硫卓、N-去甲基地尔硫卓和去乙酰地尔硫卓的平均(.+-.SD)血浆峰浓度为174.3.+-。 72.7, 42.6.+-. 10.0 和 14.9.+-。分别为3.3纳克/毫升。地尔硫卓、N-去甲基地尔硫卓和去乙酰地尔硫卓的表观半衰期为 6.5±。 1.4 小时，9.4 .+-。 2.2小时，18.+-。分别为6.2小时。 N-去甲基地尔硫卓和地尔硫卓均通过肾净分泌消除，而去乙酰地尔硫卓的肾清除率不超过滤过清除率。 N-去甲基地尔硫卓和去乙酰地尔硫卓均与血浆蛋白结合，未结合分数为 0.323.+-。 0.035 和 0.230.+-。 0.021。这些值与地尔硫卓的未结合部分相似 (0.254.+-.0.027)。地尔硫卓对血压或心率没有显着影响。然而，所有六名受试者均观察到 PR 间期延长。此外，在六名受试者中的四名中发现浓度-效应关系存在明显的顺时针滞后。这些发现表明，对地尔硫卓的电生理作用产生了某种形式的急性耐受性，但药效学模型的结果表明，这不是由代谢物的拮抗作用引起的。
A potential complicating factor in the characterization of the pharmacokinetics and pharmacodynamics of diltiazem after an oral dose is the presence of two metabolites, N-demethyldiltiazem and desacetyldiltiazem, in plasma. Both N-demethyldiltiazem and desacetyldiltiazem have been shown to have pharmacologic activity in animal tissues. It is therefore possible that these metabolites contribute to the pharmacologic effect of diltiazem, but this possibility has not been explored. The purpose of this study was to investigate the pharmacokinetics and pharmacodynamics of diltiazem, N-demethyldiltiazem, and desacetyldiltiazem. Particular attention was paid to the effect of diltiazem on atrioventricular conduction. Six healthy men received a 120 mg oral dose of diltiazem. Concentrations of diltiazem, N-demethyldiltiazem, and desacetyldiltiazem in plasma and urine were measured by a sensitive HPLC method. Measures of pharmacologic response (heart rate, blood pressure, and PR interval) were obtained at each blood sampling time. Mean (.+-. SD) peak plasma concentrations of diltiazem, N-demethyldiltiazem, and desacetyldiltiazem were 174.3 .+-. 72.7, 42.6 .+-. 10.0, and 14.9 .+-. 3.3 ng/ml, respectively. The apparent half-lives of diltiazem, N-demethyldiltiazem, and desacetyldiltiazem were 6.5 .+-. 1.4 hours, 9.4 .+-. 2.2 hours, and 18 .+-. 6.2 hours, respectively. Both N-demethyldiltiazem and diltiazem was eliminated by net renal secretion, whereas the renal clearance of desacetyldiltiazem did not exceed clearance by filtration. Both N-demethyldiltiazem and desacetyldiltiazem are bound to plasma proteins, with unbound fractions of 0.323 .+-. 0.035 and 0.230 .+-. 0.021. These values are similar to the unbound fraction of diltiazem (0.254 .+-. 0.027). No significant effect of diltiazem on blood pressure or heart rate was noted. However, a prolongation of the PR interval was observed in all six subjects. Furthermore, an apparent clockwise hysteresis in the concentration-effect relationship was found in four of the six subjects. These findings suggest that some form of acute tolerance to the electrophysiologic effect of diltiazem develops, but the results of pharmacodynamic modeling suggest that this is not caused by the antagonistic effects of the metabolites.