Rupp S M, Shinohara Y, Fisher D M, Miller R D, Castagnoli N
J Pharmacol Exp Ther. 1983 May;225(2):351-4.
The pharmacokinetics and pharmacodynamics of 4-aminopyridine (4-AP), a drug which antagonizes nondepolarizing neuromuscular blockade, were studied in seven anesthetized dogs. Using a constant infusion of pancuronium, force of the anterior tibialis contraction in response to stimulation of the sciatic nerve was depressed to 10% of the control tension (90% depression of twitch tension). After 20 min of steady state, 4-AP (1.0 mg/kg) was administered i.v. Serum, urine and bile samples were analyzed for 4-AP concentration at several intervals for 10 hr after administration of 4-AP, using a sensitive high-performance liquid chromatographic assay (1 ng/ml). Serum data best fit a three-compartment pharmacokinetic model. The volume of the central compartment was 412 +/- 352 ml/kg (mean +/- S.D.) and the volume of distribution at steady state was 2517 +/- 363 ml/kg. Initial half-lives were 1.1 +/- 0.7 and 25.4 +/- 11 min. The terminal elimination half-life was 125 +/- 23 min and total clearance was 21 +/- 4 ml/kg/min. Of the injected dose, 60 +/- 9% was recovered in the urine and only 0.01 +/- 0.01% of the dose was recovered in the bile in 10 hr. Inasmuch as renal clearance of 4-AP exceeded glomerular filtration rate we conclude that 4-AP undergoes tubular secretion into the urine. The pharmacodynamic results included an onset time of 14 +/- 8 min, peak effect (maximum percentage of antagonism of twitch tension depression) 97 +/- 27% and duration of action 219 +/- 54 min. We conclude that 4-AP has a longer serum elimination half-life and a longer and more variable duration of action than other antagonists (i.e., neostigmine and pyridostigmine) of nondepolarizing neuromuscular blockade.
在七只麻醉犬中研究了4-氨基吡啶（4-AP）的药代动力学和药效学，4-AP是一种拮抗非去极化神经肌肉阻滞的药物。通过持续输注泮库溴铵，刺激坐骨神经引起的胫前肌收缩力降低至对照张力的10%（抽搐张力降低90%）。在稳态20分钟后，静脉注射4-AP（1.0mg/kg）。在注射4-AP后10小时内的几个时间间隔，使用灵敏的高效液相色谱法（1ng/ml）分析血清、尿液和胆汁样本中的4-AP浓度。血清数据最符合三室药代动力学模型。中央室体积为412±352ml/kg（平均值±标准差），稳态分布容积为2517±363ml/kg。初始半衰期分别为1.1±0.7和25.4±11分钟。终末消除半衰期为125±23分钟，总清除率为21±4ml/kg/分钟。在10小时内，注入剂量的60±9%在尿液中回收，仅0.01±0.01%的剂量在胆汁中回收。由于4-AP的肾清除率超过肾小球滤过率，我们得出结论，4-AP经肾小管分泌进入尿液。药效学结果包括起效时间为14±8分钟，峰值效应（抽搐张力降低拮抗的最大百分比）为97±27%，作用持续时间为219±54分钟。我们得出结论，与非去极化神经肌肉阻滞的其他拮抗剂（即新斯的明和吡啶斯的明）相比，4-AP具有更长的血清消除半衰期和更长且更具变异性的作用持续时间。
