Klotz U, Antonin K H, Brügel H, Bieck P R
Clin Pharmacol Ther. 1977 Apr;21(4):430-6. doi: 10.1002/cpt1977214430.
In six patients with cirrhosis and five patients with fibrosis of the liver elimination of diazepam (D) was compared after single and subchronic dosage. The pharmacokinetics of the major metabolite desmethyldiazepam (DD) was investigated in four healthy individuals and four patients with hepatic dysfunction and compared to its parent compound D. In the initial study, 11 patients with liver disease (cirrhosis and fibrosis) had a longer half-life (T 1/2(beta) of 99.2 +/- 23.2 hr after a single intravenous bolus of 0.1 mg/kg of D than to age-matched normal subjects (46.6 +/- 14.2). After subchronic treatment with 10 mg of D for 7 days T 1/2(beta) was prolonged only slightly (p = 0.043) in these patients (107.6 +/- 25.2 hr). Neither total plasma clearance (Cl) nor the apparent volume of distribution (VdSS or VdCl) showed significant changes. After intravenous injection of DD (0.1 mg/kg) plasma levels declined in the same biexponential manner as after D. The cross-over study in the four normal subjects demonstrated that DD was eliminated much more slowly than D. Whereas for D, T 1/2(beta) and Cl were 32.6 +/- 11.3 hr and 32.3 +/- 11.0 ml/min, respectively, the corresponding values for DD were 50.9 +/- 6.2 hr and 11.3 +/- 3.1 ml/min, respectively, the corresponding values for DD were 50.9 +/- 6.2 hr and 11.3 +/- 3.1 ml/min. The accumulation of DD after multiple dosage could be explained by the fact that it is formed faster from D than it is eliminated. In four patients with liver disease the elimination of D and the elimination of DD were altered. In these patients T 1/2(beta) for DD was prolonged (p = 0.015) to 108.2 +/- 40.3 hr. This prolongation was caused by a decrease in Cl of 4.6 +/- 1.1 ml/min, (p = 0.003) whereas Vd(Cl) did not change significantly. This indicates that at least two steps in diazepam metabolism are impaired in patients with liver disease.
对6例肝硬化患者和5例肝纤维化患者在单次及亚慢性给药后地西泮（D）的消除情况进行了比较。在4名健康个体和4例肝功能不全患者中研究了主要代谢产物去甲基地西泮（DD）的药代动力学，并将其与其母体化合物D进行比较。在初始研究中，11例肝病（肝硬化和肝纤维化）患者在单次静脉推注0.1mg/kg D后，半衰期（T 1/2（β））为99.2±23.2小时，长于年龄匹配的正常受试者（46.6±14.2小时）。在以10mg D进行亚慢性治疗7天后，这些患者的T 1/2（β）仅略有延长（p = 0.043）（107.6±25.2小时）。总血浆清除率（Cl）和表观分布容积（VdSS或VdCl）均未显示出显著变化。静脉注射DD（0.1mg/kg）后，血浆水平以与注射D后相同的双指数方式下降。在4名正常受试者中进行的交叉研究表明，DD的消除比D慢得多。对于D，T 1/2（β）和Cl分别为32.6±11.3小时和32.3±11.0ml/min，而DD的相应值分别为50.9±6.2小时和11.3±3.1ml/min。多次给药后DD的蓄积可以用其从D形成的速度快于消除速度来解释。在4例肝病患者中，D和DD的消除均发生了改变。在这些患者中，DD的T 1/2（β）延长至108.2±4小时（p = 0.015）。这种延长是由Cl降低4.6±1.1ml/min引起的（p = 0.003），而Vd（Cl）没有显著变化。这表明肝病患者地西泮代谢中至少有两个步骤受损。
