Kawai H, Kokubun S, Matsumoto T, Kojima J, Onodera K
Omiya Research Laboratory, Nikken Chemicals Co., Ltd., Saitama, Japan.
Methods Find Exp Clin Pharmacol. 2000 Apr;22(3):179-84.
Aminophylline (ethylenediamine salt of theophylline) and Theodrip, a new formulation of theophylline developed by Nikken Chemicals, are drugs for the treatment of acute bronchial asthma in injectable form. The present study was conducted using dogs to first confirm the bioequivalence of the two injectable forms containing theophylline and aminophylline and to secondly clarify the influence of the rate of venous infusion on the pharmacokinetics of theophylline in plasma. The following results were obtained: 1) Pharmacokinetic parameters of plasma theophylline after an intravenous bolus injection were close to those after the dosing of aminophylline in dogs by a crossover method. Thus, the 95% confidence limits of mean value differences of Cmax, t1/2 and AUC between the two injection forms were in the range of -3.16-4.28%, -6.19-7.28% and -7.23-5.28%, respectively. These results indicate the bioequivalence between theophylline and aminophylline in dogs from a pharmacokinetic point of view as well as the lack of influence of ethylenediamine on the pharmacokinetics of theophylline. 2) After the intravenous bolus injection (30 sec) and the 15-min constant rate infusion of theophylline to dogs, the plasma concentrations of theophylline were 27.37 +/- 3.67 micrograms/ml and 18.34 +/- 2.32 micrograms/ml immediately after the completion of administration, respectively. It is notable that in humans the former concentration level has been observed to frequently cause adverse effects, whereas the latter was in the safe range. Consequently, the 15-min constant rate infusion did not result in the rapid increase in the plasma theophylline concentrations and was superior to the bolus injection from the viewpoint of maintaining the safety plasma concentrations. In conclusion, to avoid hypersensitivity due to ethylenediamine and the adverse effects caused by high plasma concentrations of theophylline, it was considered that constant rate infusion of theophylline to the venous is preferable in the clinical setting.
氨茶碱（茶碱乙二胺盐）和由日研化学公司研发的新型茶碱制剂Theodrip，均为注射用的治疗急性支气管哮喘的药物。本研究使用犬类进行，首先确认含茶碱和氨茶碱的两种注射剂的生物等效性，其次阐明静脉输注速率对犬血浆中茶碱药代动力学的影响。获得以下结果：1）静脉推注后血浆茶碱的药代动力学参数与通过交叉法给犬服用氨茶碱后的参数相近。因此，两种注射剂之间Cmax、t1/2和AUC均值差异的95%置信区间分别在-3.16 - 4.28%、-6.19 - 7.28%和-7.23 - 5.28%范围内。这些结果从药代动力学角度表明犬体内茶碱和氨茶碱之间具有生物等效性，同时也表明乙二胺对茶碱药代动力学没有影响。2）对犬静脉推注（30秒）和持续15分钟输注茶碱后，给药结束后即刻血浆茶碱浓度分别为27.37±3.67微克/毫升和18.34±2.32微克/毫升。值得注意的是，在人类中观察到前一浓度水平经常会引起不良反应，而后一浓度处于安全范围内。因此，15分钟持续输注不会导致血浆茶碱浓度快速升高，从维持安全血浆浓度的角度来看优于推注。总之，为避免因乙二胺引起的过敏反应以及高血浆浓度茶碱导致的不良反应，认为在临床环境中对静脉进行茶碱持续输注更为可取。
