Bouër R, Saivin S, Malmary M F, Hermann P, Poey J, Houin G
Laboratoire Cinétique des Xénobiotiques, Faculté des Sciences Pharmaceutiques, Toulouse, France.
Arzneimittelforschung. 1998 Jul;48(7):745-9.
The concept of proportionality between the pharmacological effects of drugs and their dosage has been questioned since the discovery of saturable phenomenon for some drug dispositions, either during their absorption or their elimination. Such saturation may also occur during the distribution phase in the tissues. This phenomenon, however, is often difficult to demonstrate and microdialysis is a powerful technique to assess precise changes in drug concentrations in tissue. This technique has been used to compare brain and blood concentrations of a potential analgesic, UP 26-91 (3-¿[2-[4-(2,4-difluorophenyl)piperazin-1-yl]ethyl]thio¿ -1,2,4-triazolo[4,3-a]pyrioline, citrate salt, CAS 115762-17-9 for the base), at different intravenous doses. Microdialysis probes were surgically implanted in the cerebral cortex and the jugular vein of male Sprague-Dawley rats (about 350 g). A single dose of radiolabelled 14(C) UP 26-91 mixed with unlabelled drug was injected into the animal's tail vein. Three doses of drug (2.5, 12.5 and 22.5 mg.kg-1) were tested, with three rats for each dose. All the doses consisted of the same amount of radiolabelled product, used as a tracer, supplemented by the amount of non-radiolabelled UP 26-91 necessary to reach the desired concentration. The rats were conscious, freely moving and had free access to food and water. Microdialysis samples were collected at the rate of 1 microliter.min-1, and sampled every 15 min for 16-17 h. The two highest doses were in the range of those used for toxicological studies. Blood UP 26-91 radioactivity concentrations were superimposable independent of the dose. Thus, it can be concluded that there was a linear relationship between blood concentrations and administered doses. By contrast, the brain concentration for the highest administered dose was statistically higher than the two others (p < 0.05), which demonstrated that UP 26-91 exhibited a non-linear pharmacokinetics in the brain. It is therefore likely that a saturable transport mechanism occurs across the blood-brain barrier. This study demonstrates that blood toxicokinetics may not correctly reflect tissue exposure to a drug.
自从发现某些药物在吸收或消除过程中存在可饱和现象以来，药物药理效应与其剂量之间的比例关系概念就受到了质疑。这种饱和现象在组织的分布阶段也可能发生。然而，这种现象往往难以证明，而微透析是评估组织中药物浓度精确变化的有力技术。该技术已被用于比较一种潜在镇痛药UP 26 - 91（3 - [2 - [4 - (2,4 - 二氟苯基)哌嗪 - 1 - 基]乙基]硫代 - 1,2,4 - 三唑并[4,3 - a]吡啶啉，柠檬酸盐，碱的CAS号为115762 - 17 - 9）在不同静脉注射剂量下的脑内和血液浓度。将微透析探针通过手术植入雄性Sprague - Dawley大鼠（约350克）的大脑皮层和颈静脉。将单剂量放射性标记的¹⁴C UP 26 - 91与未标记药物混合后注入动物尾静脉。测试了三个剂量的药物（2.5、12.5和22.5毫克·千克⁻¹），每个剂量用三只大鼠。所有剂量都含有相同量的用作示踪剂的放射性标记产物，并补充达到所需浓度所需的非放射性标记UP 26 - 91的量。大鼠处于清醒状态，可自由活动，并可自由获取食物和水。以1微升·分钟⁻¹的速率收集微透析样品，每15分钟采样一次，共采集16 - 17小时。两个最高剂量处于毒理学研究使用的剂量范围内。血液中UP 26 - 91的放射性浓度与剂量无关，呈叠加关系。因此，可以得出结论，血液浓度与给药剂量之间存在线性关系。相比之下，最高给药剂量时的脑内浓度在统计学上高于其他两个剂量（p < 0.05），这表明UP 26 - 91在脑内呈现非线性药代动力学。因此，很可能在血脑屏障上存在一种可饱和转运机制。这项研究表明，血液毒代动力学可能无法正确反映组织对药物的暴露情况。
