Physiological pharmacokinetics and pharmacodynamics of (+/-)-verapamil in female rats.
Physiological pharmacokinetics and pharmacodynamics of (+/-)-verapamil in female rats.
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DOI：
10.1002/bdd.2510080309
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发表时间：
1987-05
影响因子：
2.1
通讯作者：
E. Todd;D. Abernethy
中科院分区：
文献类型：
--
作者：
E. Todd;D. Abernethy
评价维拉帕米在稳态静脉注射中的组织分布和药效学。静脉滴注和单次给药后(Ip)。雌性SD大鼠给药情况。在一组大鼠中，维拉帕米被注入到一个稳定的浓度，在这个浓度时动物被杀死。在输注期间监测维拉帕米引起的平均动脉压(MAP)的降低，并与同时获得的维拉帕米血药浓度相关。动物处死后立即取组织(肺、肝、肾髓质、肾皮质、心肌、骨骼肌、肾周脂肪、脑干、大脑皮层和小脑)和血浆样本，测定维拉帕米和去甲维拉帕米浓度。另一组大鼠，在接受ip后。维拉帕米在1、3、5、19和24小时处死，各组织的清除按一级过程描述。维拉帕米在血浆和组织中的消除半衰期相似(1.5~2.2h)。维拉帕米不与血浆蛋白结合的百分率与浓度无关，在接受腹腔注射的大鼠之间相似。(平均值+/-S.D.)(2.28+/-0.72%)和静脉注射(2.08+/-0.03%)维拉帕米。血浆MAP与维拉帕米浓度(r=0.75；p<0.01)和心肌组织浓度(r=-0.82；p<0.01)呈极显著负相关。和IP。药品管理局。在接受腹腔注射的动物中，维拉帕米和去甲维拉帕米的组织与血浆分布比率相似。所有采样点的维拉帕米，表明已经达到了分布平衡。在稳态静脉注射后。静脉滴注维拉帕米和去甲维拉帕米组织：血药浓度比均大于ip后。行政管理。较高的组织：静脉注射后维拉帕米的血药浓度比。而不是在IP之后。政府建议，要么在I.P.之后只达到伪均衡。外消旋维拉帕米的组织分布决定因素因给药途径不同而不同。在这些研究中，MAP为维拉帕米的组织和血药浓度提供了一个合理的药效学指标。
Tissue distribution and pharmacodynamics of verapamil were evaluated during steady state intravenous (i.v.) infusion and after single dose intraperitoneal (i.p.) drug administration to female Sprague-Dawley rats. In one group of rats, verapamil was infused to a steady state concentration at which time animals were killed. Verapamil-induced decreases in mean arterial pressure (MAP) were monitored during infusion and correlated with concomitantly obtained plasma verapamil concentrations. Tissue (lung, liver, renal medulla, renal cortex, cardiac muscle, skeletal muscle, perirenal fat, brain stem, cerebral cortex, and cerebellum) and plasma samples were obtained immediately after animals were killed and verapamil and norverapamil concentrations determined. Another group of rats, after receiving i.p. verapamil, were killed at 1, 3, 5, 19, and 24 h. Elimination from each tissue evaluated was described by a first order process. Elimination half-life of verapamil was similar among plasma and tissues evaluated (1.5 to 2.2 h). The per cent verapamil not bound to plasma proteins was concentration-independent and similar between rats receiving i.p. (mean +/- S.D.) (2.28 +/- 0.72 per cent) and i.v. (2.08 +/- 0.03 per cent) verapamil. MAP and verapamil concentration in plasma (r = 0.75; p less than 0.01) and cardiac muscle (r = -0.82; p less than 0.01) were inversely correlated in a highly significant fashion during both i.v. and i.p. drug administrations. The tissue-to-plasma distribution ratio for verapamil and norverapamil was similar among animals receiving i.p. verapamil at all points of sampling, suggesting distribution equilibrium had been achieved. After steady state i.v. infusion, both verapamil and norverapamil tissue: plasma concentration ratios were greater than after i.p. administration. Higher tissue: plasma verapamil concentration ratios after i.v. administration than after i.p. administration suggest either only a pseudoequilibrium is attained after i.p. administration or that determinants of tissue distribution of racemic verapamil differ with different routes of drug administration. In these studies, MAP provided a reasonable pharmacodynamic marker for verapamil tissue and plasma concentrations.