Yeung P K, Feng J D, Buckley S J
College of Pharmacy and Department of Medicine, Faculty of Health Professions, Dalhousie University, Halifax, Nova Scotia, Canada.
J Pharm Pharmacol. 1998 Nov;50(11):1247-53. doi: 10.1111/j.2042-7158.1998.tb03341.x.
To assess the contribution of its metabolites to the antihypertensive effects of diltiazem, a previously established rabbit model has been used to compare the pharmacokinetics and haemodynamic effects of the drug with those of its major metabolites deacetyldiltiazem (M1) and deacetyl-N-monodemethyldiltiazem (M2). Diltiazem, M1 and M2 were administered separately to each animal (n = 5 or 6 per study group) as a single 5 mg kg(-1) intravenous dose. Blood samples, systolic and diastolic blood pressure (SBP and DBP) and heart rate were recorded for each rabbit up to 8 h, and urine samples were collected for 48 h post-dose. Plasma concentrations of diltiazem and its major metabolites were determined by HPLC. The results showed that systemic clearance (CL) and volume of distribution at steady state (Vdss) were smaller for diltiazem than for the metabolites. Diltiazem and the metabolites reduced both SBP and DBP, the effects of diltiazem being most potent. Their effects on heart rate were highly variable and not statistically different between treatment groups (P > 0.05). These results indicate that diltiazem is a more potent hypotensive agent than M1 or M2, possibly because of the higher plasma concentrations secondary to the smaller CL and Vdss of diltiazem compared with the metabolites. The effects of the metabolites might, however, be more sustained.
为评估地尔硫䓬代谢产物对其降压作用的贡献，已使用先前建立的兔模型比较该药物与其主要代谢产物去乙酰地尔硫䓬（M1）和去乙酰 - N - 单去甲基地尔硫䓬（M2）的药代动力学和血流动力学效应。将地尔硫䓬、M1和M2分别以5 mg kg(-1) 的单次静脉注射剂量给予每只动物（每个研究组n = 5或6）。在长达8小时内记录每只兔子的血样、收缩压和舒张压（SBP和DBP）以及心率，并在给药后48小时收集尿样。用地尔硫䓬及其主要代谢产物的血浆浓度通过高效液相色谱法测定。结果表明，地尔硫䓬的全身清除率（CL）和稳态分布容积（Vdss）比代谢产物小。地尔硫䓬及其代谢产物均降低SBP和DBP，地尔硫䓬的作用最为显著。它们对心率的影响变化很大，各治疗组之间无统计学差异（P > 0.05）。这些结果表明，地尔硫䓬是比M1或M2更有效的降压药，可能是因为与代谢产物相比，地尔硫䓬的CL和Vdss较小，导致血浆浓度较高。然而，代谢产物的作用可能更持久。
