Katayama K, Ohtani H, Murai A, Kakemi M, Koizumi T
Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Japan.
J Pharmacobiodyn. 1990 Feb;13(2):108-19. doi: 10.1248/bpb1978.13.108.
In order to evaluate dose-dependent sulfamethizole (SMZ) kinetics, 100, 300 and 1000 mg of SMZ was constantly infused over 5 min in rabbits and thereafter plasma and urine samples were collected at convenient intervals. When a dose of 100 mg was given, the time course of total plasma concentration followed a biexponential characteristic. For higher doses, plasma decay curves revealed a convex descending feature after the distribution phase. The respective unbound fraction in plasma (fp) at the total plasma concentrations of 200 and 100 micrograms/ml were 0.41 and 0.19. The corresponding total body clearances were 2.6 and 2.2 l/h, indicating that the drug elimination did not contribute to the convex-descending plasma curves. A physiologically based pharmacokinetic model was adapted to various tissue levels of SMZ. No saturable tissue binding was observed and the apparent volume of distribution of SMZ at steady state with a rabbit of 3.3 kg, Vss (1), calculated by tissue volumes and partition coefficients of tissue to unbound plasma was expressed as follows: Vss = 0.14 + 1.86fp. From this relationship, it was shown that the apparent volume of distribution of SMZ was significantly affected by the unbound fraction in plasma and the dose-dependent kinetics after intravenous administration was due to the decrease of the apparent volume of distribution with time. The tissue distribution study contributed significantly to the understanding of the dose-dependent drug kinetics.
为了评估磺胺甲噻二唑（SMZ）的剂量依赖性动力学，分别给家兔静脉注射100、300和1000mg的SMZ，持续5分钟，随后在适当的时间间隔采集血浆和尿液样本。给予100mg剂量时，血浆总浓度的时间过程呈双指数特征。对于更高的剂量，血浆衰减曲线在分布相后显示出凸形下降特征。在血浆总浓度为200和100μg/ml时，相应的血浆中未结合分数（fp）分别为0.41和0.19。相应的总体清除率分别为2.6和2.2 l/h，表明药物消除对血浆曲线的凸形下降没有影响。将基于生理的药代动力学模型应用于SMZ在各种组织中的水平。未观察到可饱和的组织结合，对于一只体重3.3kg的家兔，通过组织体积和组织与未结合血浆的分配系数计算得到的稳态下SMZ的表观分布容积Vss(1)如下：Vss = 0.14 + 1.86fp。从这种关系可以看出，SMZ的表观分布容积受血浆中未结合分数的显著影响，静脉给药后的剂量依赖性动力学是由于表观分布容积随时间的减少所致。组织分布研究对理解剂量依赖性药物动力学有很大帮助。
