Thiollier Thibaud, Wu Caisheng, Contamin Hugues, Li Qin, Zhang Jinlan, Bezard Erwan
Cynbiose, Marcy l'Etoile, France.
Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux, France.
Synapse. 2016 Jun;70(6):231-9. doi: 10.1002/syn.21889. Epub 2016 Mar 15.
Brain bioavailability of drugs developed to address central nervous system diseases is classically documented through cerebrospinal fluid collected in normal animals, i.e., through an approximation as there are fundamental differences between cerebrospinal fluid and tissue contents. The fact that disease might affect brain availability of drugs is almost never considered at this stage although several conditions are associated with blood-brain barrier damage. Building upon our expertise in Parkinson's disease translational research, the present study addressed this gap comparing plasma and cerebrospinal fluid bioavailability of l-3,4-dihydroxyphenylalanine, carbamazepine, quinidine, lovastatin, and simvastatin, in healthy and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated macaques, the gold standard model of Parkinson's disease. The drugs were selected based upon their differential transport across the blood-brain barrier. Interestingly, brain bioavailability of quinidine was decreased while others were unaffected. Pharmacokinetics and pharmacodynamics experiments of drugs addressing Parkinson's disease might thus be performed in healthy animals unless the drugs are known to interact with the organic cation transporter.
用于治疗中枢神经系统疾病的药物的脑生物利用度，传统上是通过收集正常动物的脑脊液来记录的，也就是说，这只是一种近似方法，因为脑脊液和组织成分之间存在根本差异。尽管有几种情况与血脑屏障损伤有关，但在这个阶段几乎从未考虑过疾病可能会影响药物的脑生物利用度。基于我们在帕金森病转化研究方面的专业知识，本研究通过比较健康和1-甲基-4-苯基-1,2,3,6-四氢吡啶处理的猕猴（帕金森病的金标准模型）中左旋多巴、卡马西平、奎尼丁、洛伐他汀和辛伐他汀的血浆和脑脊液生物利用度，填补了这一空白。这些药物是根据它们在血脑屏障上的不同转运情况来选择的。有趣的是，奎尼丁的脑生物利用度降低，而其他药物则不受影响。因此，除非已知药物与有机阳离子转运体相互作用，否则针对帕金森病的药物的药代动力学和药效学实验可能在健康动物中进行。
