Jolliet-Riant P, Boukef M F, Duché J C, Simon N, Tillement J P
Service de Pharmacologie, Faculté de Médecine de Créteil-Paris XII, Creteil, France.
Life Sci. 1998;62(14):PL219-26. doi: 10.1016/s0024-3205(98)00061-7.
The objective of this work was to check the effects of alpha-1 acid glycoprotein (AAG) and of its components, A and F1/S genetic variants, on the brain transfer of drugs they bind in plasma. The relevant extractions of six basic drugs, highly bound to AAG, were measured. We chose three drugs selectively bound to the A variant, disopyramide, imipramine and methadone, one drug mainly bound to the mixture F1/S, mifepristone, and two drugs which were simultaneously bound to the variant A and the mixture F1/S, propranolol and chlorpromazine. Their brain extraction were investigated in rats using the carotid injection technique and the capillary depletion method. Injected drugs were dissolved either in buffer, either in native AAG containing the three variants (A, F1 and S), either in variant A or in variant F1/S solutions. Brain extractions of disopyramide, imipramine and methadone were significantly reduced by native AAG and by variant A. Drug's plasma retention was related to their preferential and almost exclusive binding to A variant, both of them exhibiting the same decrease in brain transfer as compared to a buffered solution. At the opposite, there were no significative differences between the extraction either in buffer, either in AAG or in F1/S solutions, of drugs both bound to A variant and F1/S mixture (chlorpromazine and propranolol) or to the F1/S mixture (mifepristone). In serum, the retentional effect of the A variant on the extraction of disopyramide and imipramine was counteracted by the presence of albumin and lipoproteins, which simultaneously bind these two drugs at a high extent and act as permissive binders. We conclude that AAG binding decreases brain drug transfer when the A variant is mainly and almost exclusively involved in the binding. On the contrary, the entire fraction of the tested drugs when bound exclusively or partly to the mixture F1/S is available for transfer into the brain.
本研究的目的是检验α-1酸性糖蛋白（AAG）及其组分A和F1/S基因变体对其在血浆中结合的药物脑转运的影响。测定了六种与AAG高度结合的碱性药物的相关提取率。我们选择了三种选择性结合A变体的药物，即丙吡胺、丙咪嗪和美沙酮，一种主要结合F1/S混合物的药物，即米非司酮，以及两种同时结合A变体和F1/S混合物的药物，即普萘洛尔和氯丙嗪。采用颈动脉注射技术和毛细血管耗竭法在大鼠中研究了它们的脑提取率。注射的药物分别溶解在缓冲液中、含有三种变体（A、F1和S）的天然AAG中、变体A溶液或变体F1/S溶液中。天然AAG和变体A显著降低了丙吡胺、丙咪嗪和美沙酮的脑提取率。药物在血浆中的滞留与其对A变体的优先且几乎排他性结合有关，与缓冲溶液相比，二者在脑转运中均表现出相同程度的降低。相反，同时结合A变体和F1/S混合物（氯丙嗪和普萘洛尔）或F1/S混合物（米非司酮）的药物，在缓冲液、AAG溶液或F1/S溶液中的提取率没有显著差异。在血清中，白蛋白和脂蛋白的存在抵消了A变体对丙吡胺和丙咪嗪提取的滞留作用，白蛋白和脂蛋白同时大量结合这两种药物并起到允许性结合剂作用。我们得出结论，当主要且几乎排他性地涉及A变体结合时，AAG结合会降低脑内药物转运。相反，测试药物中专门或部分结合F1/S混合物的整个部分可用于转运至脑内。
