Diltiazem pharmacokinetics in the rat and relationship between its serum concentration and uterine and cardiovascular effects
Diltiazem pharmacokinetics in the rat and relationship between its serum concentration and uterine and cardiovascular effects
复制标题
地尔硫卓在大鼠体内的药代动力学及其血药浓度与子宫和心血管效应的关系
DOI：
10.1111/j.1476-5381.1987.tb11271.x
复制
发表时间：
1987
影响因子：
7.3
通讯作者：
M. Hollingsworth
中科院分区：
文献类型：
--
作者：
S. Downing;D. Edwards;M. Hollingsworth
1 在卵巢切除 (ovx) 未妊娠和完整妊娠晚期麻醉大鼠中进行静脉推注后研究地尔硫卓的动力学。注射（2 mg kg−1）并在 180 分钟静脉内注射。输注（50 μg kg−1 min−1 和 100 μg kg−1 min−1）。测量非妊娠大鼠的子宫收缩、平均血压和心率。图 2 静脉推注后血清地尔硫卓浓度的测量ovx非怀孕大鼠中的注射显示出随时间的双指数衰减，由此计算出以下参数：分布面积体积（V（面积））-256±46ml；速率常数 k12 − 0.46 ± 0.10 min−1； k21−0.09±0.01min−1； kel-0.13±0.03min-1；消除清除率− 3.2 ± 0.3 ml min−1；分布 t1/2 (t1/2α) − 1.4 ± 0.3 分钟；消除 t1/2 (t1/2β) − 61.2 ± 13.0 分钟在怀孕大鼠中，也观察到双指数衰减，其参数与非怀孕动物相似，除了 V（面积）- 1004 ± 184 ml 显着增加； kel − 0.54 ± 0.16 min−1 和消除间隙 − 14.8 ± 2.3 ml min−1。 3 在非妊娠 ovx 大鼠中，输注期间血清地尔硫卓浓度的测量得出以下参数：V(ss) − 79 ± 10 ml；速率常数 k12 − 1.02 ± 0.21 min−1； k21−0.03±0.01min−1； kel‐0.39 ± 0.06 min−1；消除清除率‐7.8 ± 1.2 ml min−1。在怀孕大鼠中，观察到 kel − 1.25 ± 0.38 min−1 和消除清除率 − 36.4 ± 13.8 ml min−1 显着增加。 4 静脉推注后观察到子宫收缩、平均血压和心率立即减少。注射地尔硫卓，随着血清地尔硫卓浓度下降而返回到对照值。 3 个参数的抑制作用与地尔硫卓血清浓度对数之间存在显着相关性。血清浓度-反应曲线显示抑制子宫收缩的IC50值为0.5 μg ml−1，降低血压的IC50值为0.7 μg ml−1，降低心率的IC50值为1.2 μg ml−1。输注期间子宫收缩积分、平均血压和心率持续降低。 5 静脉注射后很少检测到代谢物去乙酰地尔硫卓。推注后，在 5/13 的注射地尔硫卓的大鼠中未发现这种现象，但在所有大鼠中均观察到对子宫收缩的显着抑制。作为大鼠离体子宫收缩抑制剂，地尔硫卓的效力比去乙酰地尔硫卓强 3.2 倍。 6 这些发现表明，子宫收缩的抑制是由于地尔硫卓的直接作用，而不是代谢物去乙酰地尔硫卓，并且表明与心血管作用相比，子宫收缩的选择性仅有轻微。
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 μg kg−1 min−1 and 100 μg 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 (t1/2α) − 1.4 ± 0.3 min; elimination t1/2 (t1/2β) − 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 μg ml−1 for inhibition of uterine contractions, 0.7 μg ml−1 for reduction in blood pressure and 1.2 μg 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.
血浆中地尔硫卓及其代谢物的高效液相色谱分析
DOI：
10.1016/s0378-4347(00)86111-3
发表时间：
1983
期刊：
Journal of chromatography
影响因子：
--
作者：
Verghese,C;Smith,MS;Aanonsen,L;Pritchett,EL;Shand,DG
通讯作者：
Shand,DG