Kölle E U, Ochs H R, Vollmer K O
Arzneimittelforschung. 1983;33(7):972-7.
The pharmacokinetic profile of D-3-acetoxy-cis-2,3-dihydro-5-(2-dimethylamino-ethyl)-2-(p-methoxy-phenyl)-1, 5-benzothiazepin-4(5H)-one hydrochloride (diltiazem . HCl) following i.v. and p.o. administration has been studied in six healthy subjects using a new sensitive GLC method. The volunteers received an i.v. infusion of 20 mg in 20 min, a peroral solution of 120 mg and two 60-mg tablets (Dilzem) in a randomized sequence. The plasma level time courses of the unchanged compound following infusion and peroral solution were simultaneously evaluated by nonlinear regression analysis. The best model was chosen by means of statistical criteria. In all subjects the experimental data could be adequately described by an open three-compartment model with zero order input following infusion and first order absorption following p.o. solution. Using this procedure the following common disposition parameters were obtained for both routes of administration: t1/2 alpha = 0.1 h, t1/2 beta = 2.1 h, t1/2 gamma = 9.8 h (harmonic means derived from individualized fits), Vc = 0.9 +/- 0.4 l/kg, Vss = 5.2 +/- 2.4 l/kg, Cltot = 11.5 +/- 1.8 ml/min/kg. Compared to the beta-phase the terminal gamma phase represents a smaller contribution to the total AUC. The blood/plasma distribution ratio was found to be 1.00 +/- 0.08 (N = 4), the mean hepatic extraction ratio was 0.54. Peak levels appeared 0.6 +/- 0.3 h after the p.o. solution. The mean absolute bioavailability of diltazem based on the individual AUC infinity 0 of the p.o. solution and the infusion was 0.44 +/- 0.10. Following tablet administration, delayed maximum levels were found after 2.8 +/- 0.9 h. Comparing the AUC infinity 0 of tablets and p.o. solution, there was no significant difference between both dosage forms.
采用一种新的灵敏气相色谱法，在6名健康受试者身上研究了盐酸地尔硫䓬（D - 3 - 乙酰氧基 - 顺式 - 2,3 - 二氢 - 5 - (2 - 二甲氨基乙基) - 2 - (对甲氧基苯基) - 1,5 - 苯并硫氮杂䓬 - 4(5H) - 酮盐酸盐）静脉注射和口服给药后的药代动力学特征。志愿者按随机顺序接受20分钟内静脉输注20毫克、口服120毫克溶液以及两片60毫克片剂（地尔硫䓬）。通过非线性回归分析同时评估输注和口服溶液后未变化化合物的血浆浓度 - 时间过程。借助统计标准选择最佳模型。在所有受试者中，实验数据可用开放三室模型充分描述，输注后为零级输入，口服溶液后为一级吸收。采用该方法获得了两种给药途径的以下共同处置参数：t1/2α = 0.1小时，t1/2β = 2.1小时，t1/2γ = 9.8小时（由个体拟合得出的调和均值），Vc = 0.9±0.4升/千克，Vss = 5.2±2.4升/千克，Cltot = 11.5±1.8毫升/分钟/千克。与β相相比，终末γ相对总AUC的贡献较小。发现血/血浆分布比为1.00±0.08（N = 4），平均肝提取率为0.54。口服溶液后0.6±0.3小时出现峰值水平。基于口服溶液和输注的个体AUC∞0，地尔硫䓬的平均绝对生物利用度为0.44±0.10。片剂给药后，在2.8±0.9小时后发现延迟的最大水平。比较片剂和口服溶液的AUC∞0，两种剂型之间无显著差异。
