Anderson J L, Patterson E, Wagner J G, Stewart J R, Behm H L, Lucchesi B R
Clin Pharmacol Ther. 1980 Oct;28(4):468-78. doi: 10.1038/clpt.1980.190.
To compare the oral and intravenous disposition of bretylium tosylate in man, 10 normal male subjects were randomly assigned single doses of 5 mg/kg bretylium tosylate either orally or intravenously and crossed over 2 wk later to the opposite route (20 studies). Each experiment included sampling for drug in serum and urine over 48 hr. Bretylium tosylate was assayed by gas chromatography. Kinetic analysis provided the following mean [coefficient of variation] results: 100FPo, 22.6% [40.2%]; ClrIV, 300 ml/min [27.8%]; ClrPo, 1.268 mg/min [54.8%]; ClBIV, 299 ml/min [31.9%]; f, 101% [8.7%]; Vdss, 3.37 l/kg [30.5%]; lambda lIV 0.0510 [12.8%]; lambda lPG, 0.115 [52.7%]hr-1; elimination half-life (t 1/2) after intravenous bretylium tosylate, 13.6 hr, and after oral bretylium tosylate, 6.0 hr (harmonic means). Bretylium tosylate binding to plasma proteins in normal volunteer samples was found to be negligible. The results indicate extensive tissue binding of bretylium tosylate. Oral doses of bretylium tosylate are only partially absorbed. Bretylium tosylate is eliminated entirely by the kidneys as unchanged drug. The greater renal clearance after oral than intravenous bretylium tosylate, and the greater elimination rate constant and shorter oral bretylium tosyulate t 1/2 are of interest but no explanation is available.
为比较托西溴苄铵在人体中的口服和静脉处置情况，10名正常男性受试者被随机分配，分别口服或静脉给予5mg/kg的托西溴苄铵单剂量，并在2周后交叉至相反给药途径（共20项研究）。每项实验包括在48小时内采集血清和尿液样本进行药物检测。托西溴苄铵采用气相色谱法进行测定。动力学分析得出以下平均[变异系数]结果：口服生物利用度，22.6% [40.2%]；静脉清除率，300ml/min [27.8%]；口服清除率，1.268mg/min [54.8%]；静脉分布容积清除率，299ml/min [31.9%]；口服生物利用度，101% [8.7%]；稳态分布容积，3.37l/kg [30.5%]；静脉消除速率常数，0.0510 [12.8%]；口服消除速率常数，0.115 [52.7%]hr-1；静脉注射托西溴苄铵后的消除半衰期（t1/2）为13.6小时，口服托西溴苄铵后的消除半衰期为6.0小时（调和均值）。在正常志愿者样本中，发现托西溴苄铵与血浆蛋白的结合可忽略不计。结果表明托西溴苄铵在组织中广泛结合。口服托西溴苄铵仅部分被吸收。托西溴苄铵以原形药物完全经肾脏消除。口服托西溴苄铵后的肾脏清除率高于静脉注射，且口服消除速率常数更大、口服托西溴苄铵的t1/2更短，这很有意思，但尚无解释。
