地尔硫䓬在大鼠体内的药代动力学及其血清浓度与子宫和心血管效应之间的关系。

Diltiazem pharmacokinetics in the rat and relationship between its serum concentration and uterine and cardiovascular effects.

作者信息

Downing S J, Edwards D, Hollingsworth M

机构信息

Department of Physiological Sciences, University of Manchester, Oxford.

出版信息

Br J Pharmacol. 1987 Aug;91(4):735-45. doi: 10.1111/j.1476-5381.1987.tb11271.x.

DOI:10.1111/j.1476-5381.1987.tb11271.x

PMID:3664075

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1853582/

Abstract

1 The kinetics of diltiazem were investigated in ovariectomized (ovx) non-pregnant and intact late pregnant anaesthetized rats following a bolus i.v. injection (2 mg kg-1) and during a 180 min i.v. infusion (50 micrograms kg-1 min-1 and 100 micrograms kg-1 min-1). Uterine contractions, mean blood pressure and heart rate were measured in the non-pregnant rats. 2 Measurement of serum diltiazem concentrations after bolus i.v. injection in ovx non-pregnant rats showed a biexponential decay with time from which the following parameters were calculated: volume of distribution area (V(area)) - 256 +/- 46 ml; rate constants k12 - 0.46 +/- 0.10 min-1; k21 - 0.09 +/- 0.01 min-1; kel - 0.13 +/- 0.03 min-1; elimination clearance - 3.2 +/- 0.3 ml min-1; distribution t1/2 (t1/2) - 1.4 +/- 0.3 min; elimination t1/2 (t1/2 beta) - 61.2 +/- 13.0 min. In pregnant rats, a biexponential decay was also observed with similar parameters to those in non-pregnant animals except for markedly increased V(area) - 1004 +/- 184 ml; kel - 0.54 +/- 0.16 min-1 and elimination clearance - 14.8 +/- 2.3 ml min-1. 3 Measurement of serum diltiazem concentrations during infusion yielded the following parameters in non-pregnant ovx rats: V(ss)--79 +/- 10 ml; rate constants k12 - 1.02 +/- 0.21 min-1; k21 - 0.03 +/- 0.01 min-1; kel - 0.39 +/- 0.06 min-1; elimination clearance - 7.8 +/- 1.2 ml min-1. In pregnant rats a marked increase was observed in kel - 1.25 +/- 0.38 min-1 and elimination clearance - 36.4 +/- 13.8 ml min-1. 4 An immediate reduction in uterine contractions, mean blood pressure and heart rate was observed after bolus i.v. injection of diltiazem with a return towards control values as serum diltiazem concentrations declined. There were significant correlations between the inhibition of the 3 parameters and the log serum concentrations of diltiazem. Serum concentration-response curves indicated IC50 values of 0.5 microgram ml-1 for inhibition of uterine contractions, 0.7 microgram ml-1 for reduction in blood pressure and 1.2 micrograms ml-1 for reduction in heart rate. There were maintained reductions in the integral of uterine contractions, mean blood pressure and heart rate during infusion. 5 The metabolite desacetyldiltiazem was rarely detected after i.v. bolus injection and was not found in 5/13 rats infused with diltiazem, yet significant inhibition of uterine contractions was observed in all rats. Diltiazem was 3.2 fold more potent than desacetyldiltiazem as an inhibitor of contractions of the rat isolated uterus. 6 These findings indicate that the inhibition of uterine contractions is due to a direct action of diltiazem, and not the metabolite desacetyldiltiazem, and suggest only a slight selectivity for uterine inhibition compared to cardiovascular effects.

摘要

在切除卵巢（ovx）的未孕和完整的晚期妊娠麻醉大鼠中，静脉推注（2 mg/kg）后以及在180分钟静脉输注（50 μg/kg·min⁻¹和100 μg/kg·min⁻¹）期间，研究了地尔硫䓬的动力学。在未孕大鼠中测量子宫收缩、平均血压和心率。
对ovx未孕大鼠静脉推注后测量血清地尔硫䓬浓度，显示其随时间呈双指数衰减，据此计算出以下参数：分布容积（V(area)） - 256 ± 46 ml；速率常数k12 - 0.46 ± 0.10 min⁻¹；k21 - 0.09 ± 0.01 min⁻¹；kel - 0.13 ± 0.03 min⁻¹；消除清除率 - 3.2 ± 0.3 ml/min；分布半衰期（t1/2） - 1.4 ± 0.3 min；消除半衰期（t1/2β） - 61.2 ± 13.0 min。在妊娠大鼠中，也观察到双指数衰减，除V(area)显著增加至1004 ± 184 ml、kel - 0.54 ± 0.16 min⁻¹和消除清除率 - 14.8 ± 2.3 ml/min外，其他参数与未孕动物相似。
在输注期间测量血清地尔硫䓬浓度，未孕ovx大鼠得出以下参数：稳态分布容积（V(ss)）--79 ± 10 ml；速率常数k12 - 1.02 ± 0.21 min⁻¹；k21 - 0.03 ± 0.01 min⁻¹；kel - 0.39 ± 0.06 min⁻¹；消除清除率 - 7.8 ± 1.2 ml/min。在妊娠大鼠中，观察到kel显著增加至1.25 ± 0.38 min⁻¹和消除清除率 - 36.4 ± 13.8 ml/min。
静脉推注地尔硫䓬后，立即观察到子宫收缩、平均血压和心率降低，随着血清地尔硫䓬浓度下降，这些指标恢复至对照值。这三个参数的抑制与地尔硫䓬的对数血清浓度之间存在显著相关性。血清浓度 - 反应曲线表明，抑制子宫收缩的IC50值为0.5 μg/ml，降低血压的IC50值为0.7 μg/ml，降低心率的IC50值为1.2 μg/ml。在输注期间，子宫收缩积分、平均血压和心率持续降低。
静脉推注后很少检测到代谢产物去乙酰地尔硫䓬，在13只输注地尔硫䓬的大鼠中有5只未检测到该代谢产物，但在所有大鼠中均观察到子宫收缩受到显著抑制。作为大鼠离体子宫收缩抑制剂，地尔硫䓬的效力比去乙酰地尔硫䓬高3.2倍。
这些发现表明，子宫收缩的抑制是由于地尔硫䓬的直接作用，而非代谢产物去乙酰地尔硫䓬的作用，并且与心血管效应相比，对子宫抑制的选择性仅略有差异。