Garrett E R, Green J R, Bialer M
Biopharm Drug Dispos. 1982 Apr-Jun;3(2):129-64. doi: 10.1002/bdd.2510030206.
The pharmacokinetics and bioavailabilities of bretylium tosylate were studied in 9 male normal volunteers by 60 min constant rate intravenous infusions of 200, 300, and 400 mg, by intramuscular injection of 300 and 400 mg, by oral administration of 100, 200, and 400 mg in solution, and by oral administration of 200 mg tablets. The latter studies were repeated in the same 5 volunteers which were also studied by all modes of administration and at several doses. Intravenous studies showed a sum of 3 exponentials to characterize plasma level-time studies with a terminal half-life of 535 +/- 32 (S.E.M.) min (n = 12). The urinary recovery of unchanged drug was 77 +/- 4(S.E.M.)(n = 14). Half-lives within a subject were correlated and independent of dose. Intramuscular administration showed an apparent half-life of first-order invasion of 79 +/- 13 (S.E.M.) min (n = 6) with no apparent dose dependency and a urinary recovery of unchanged drug of 95.4 +/- 3.2 (S.E.M.) per cent with a terminal half-life similar to the intravenous studies. Oral solutions had smaller lag times of absorption [17 +/- 4(S.E.M.) min] than tablets [56 +/- 9 (S.E.M.) min] and longer apparent half-lives of first-order absorption [231 +/- 23 (S.E.M.) min] than tablets [87 +/- 15 (S.E.M.) min]. The tablets had slightly greater bioavailabilities [27 +/- 2.3 (S.E.M.) per cent] than the oral solutions [22.1 +/- 2.2 (S.E.M.) per cent] but with no apparent dose dependencies. Renal clearances were the same for all modes of administration. Means +/- S.E.M. were 735 +/- 32, i.v., 686 +/- 38, i.m., and 623 +/- 57 ml min-1, p.o. Apparent overall volumes of distribution were 589 +/- 401, i.v. and 450 +/- 671 (S.E.M.), i.m. The i.v. studies in three dogs confirmed the three-compartment body model and the high overall volumes of distribution, had terminal half-lives similar to humans and had renal clearances of 84, 164, and 207 ml min-1 that were in excess of glomerular filtration. There were no significant changes of cardiovascular parameters with the time course of the drug in the body and no significant drug-affected clinical parameters. The only consistent side effect was a generally transient nasal congestion at plasma peak time on intravenous administration.
在9名男性正常志愿者中，通过以60分钟恒速静脉输注200、300和400毫克、肌肉注射300和400毫克、口服100、200和400毫克溶液以及口服200毫克片剂的方式，研究了甲苯磺酸溴苄铵的药代动力学和生物利用度。后一项研究在相同的5名志愿者中重复进行，这些志愿者也通过所有给药方式和几种剂量进行了研究。静脉研究显示，用3个指数之和来表征血浆浓度-时间研究，终末半衰期为535±32（标准误）分钟（n = 12）。原形药物的尿回收率为77±4（标准误）（n = 14）。受试者体内的半衰期相互关联且与剂量无关。肌肉注射显示一级吸收的表观半衰期为79±13（标准误）分钟（n = 6），无明显剂量依赖性，原形药物的尿回收率为95.4±3.2（标准误）%，终末半衰期与静脉研究相似。口服溶液的吸收滞后时间[17±4（标准误）分钟]比片剂[56±9（标准误）分钟]短，一级吸收的表观半衰期[231±23（标准误）分钟]比片剂[87±15（标准误）分钟]长。片剂的生物利用度[27±2.3（标准误）%]略高于口服溶液[22.1±2.2（标准误）%]，但无明显剂量依赖性。所有给药方式的肾清除率相同。静脉给药的平均值±标准误为735±32、肌肉注射为686±38、口服为623±57毫升/分钟。静脉给药的表观总体分布容积为589±401，肌肉注射为450±671（标准误）。在三只犬身上进行的静脉研究证实了三室模型和高总体分布容积，终末半衰期与人类相似，肾清除率分别为84、164和207毫升/分钟，超过了肾小球滤过率。随着药物在体内的时间进程，心血管参数无显著变化，也没有受药物影响的显著临床参数。唯一一致的副作用是静脉给药时在血浆峰值时间普遍出现的短暂性鼻充血。
