Müller P, Flesch G, de Gasparo M, Gasparini M, Howald H
Clinical Pharmacology, Novartis Pharma AG, Basel, Switzerland.
Eur J Clin Pharmacol. 1997;52(6):441-9. doi: 10.1007/s002280050317.
Pharmacokinetics, pharmacodynamic effects and tolerability of 200 mg valsartan, once-daily for 8 days, were investigated in 16 healthy, normotensive volunteers on a normal sodium diet.
This was a double-blind, placebo-controlled, randomized crossover study. Drug concentrations in plasma and urine, angiotensin II (Ang II) concentrations in plasma, systolic (SBP) and diastolic (DBP) blood pressure, heart rate (HR) in the supine position and 3 min after passive head-up tilting, as well as safety parameters (ECG, clinical chemistry and hematology, renal water and electrolyte excretion) were measured over 24 h after the first dose (day 1) and at steady state on day 8.
Absorption and distribution of valsartan were rapid (Cmax, 2 h; t1/2 lambda 1 < 1 h), followed by a slower terminal elimination phase (t1/2 lambda 2, 6 h) on days 1 and 8, with little accumulation in plasma (increase of 20% on day 8). Less than 10% of the dose was excreted unchanged in urine. The increase in plasma Ang II (Cmax, 6 h) was significantly enhanced at steady state. Supine SBP and DBP significantly decreased on day 8 only, by an average of -3.6 and -2.4 mmHg, respectively, versus placebo, without a concomitant increase in HR. Upon passive tilting, the increase in DBP, normally reinforced by sympathetic renin release, was slightly but significantly blunted on day 1 (-2.0 mmHg) and day 8 (-4.0 mmHg) of treatment with valsartan versus placebo. The orthostatic reflex increase in HR was slightly enhanced compared with placebo by an average of 2.8 beats min-1 on day 1 and by 2.9 beats.min-1 on day 8. Valsartan was well tolerated and had no influence on ECG, clinical laboratory parameters, and water, electrolyte and uric acid excretion.
Pharmacokinetics of valsartan are unchanged after multiple once-daily dosing, with little (expected) accumulation in plasma. Effects of 200 mg valsartan on blood pressure in healthy subjects on a normal sodium intake are small and become more prominent after repeated dosing. Indirect evidence of AT1 blockade by valsartan is demonstrated by an increase of plasma Ang II and by a blunted DBP response to passive tilting. The decrease in blood pressure at steady state enhances the increase in plasma Ang II. Valsartan is well tolerated and is devoid of effects on water, electrolyte and uric acid excretion at 200 mg per day in healthy normotensive volunteers.
在16名正常钠饮食的健康血压正常志愿者中，研究了每日一次服用200毫克缬沙坦，连续服用8天的药代动力学、药效学作用及耐受性。
这是一项双盲、安慰剂对照、随机交叉研究。在首剂给药后24小时（第1天）和第8天稳态时，测量血浆和尿液中的药物浓度、血浆中血管紧张素II（Ang II）浓度、仰卧位收缩压（SBP）和舒张压（DBP）、心率（HR）以及被动头高位倾斜3分钟后的心率，以及安全参数（心电图、临床化学和血液学、肾脏水和电解质排泄）。
缬沙坦的吸收和分布迅速（Cmax为2小时；t1/2λ1<1小时），在第1天和第8天随后是较慢的终末消除期（t1/2λ2为6小时），血浆中几乎没有蓄积（第8天增加20%）。不到10%的剂量以原形从尿液中排泄。稳态时血浆Ang II的升高（Cmax为6小时）显著增强。仅在第8天，仰卧位SBP和DBP显著下降，与安慰剂相比，平均分别下降-3.6和-2.4 mmHg，心率没有随之增加。被动倾斜时，通常由交感肾素释放增强的DBP升高，在缬沙坦治疗的第1天（-2.0 mmHg）和第8天（-4.0 mmHg）与安慰剂相比略有但显著减弱。与安慰剂相比，直立反射引起的HR增加在第1天平均增加2.8次/分钟，在第8天平均增加2.9次/分钟，略有增强。缬沙坦耐受性良好，对心电图、临床实验室参数以及水、电解质和尿酸排泄没有影响。
缬沙坦每日一次多次给药后药代动力学不变，血浆中几乎没有（预期的）蓄积。200毫克缬沙坦对正常钠摄入的健康受试者血压的影响较小，重复给药后作用更明显。血浆Ang II升高以及DBP对被动倾斜反应减弱证明了缬沙坦对AT1的阻断作用的间接证据。稳态时血压下降增强了血浆Ang II的升高。缬沙坦耐受性良好，对健康血压正常志愿者每日200毫克剂量下的水、电解质和尿酸排泄没有影响。
