Chabenat C, Chretien P, Daoust M, Moore N, Andre D, Lhuintre J P, Saligaut C, Boucly P, Boismare F
Centre de Pharmacochimie, UER de Médecine-Pharmacie de Rouen, Saint-Etienne du Rouvray, France.
Methods Find Exp Clin Pharmacol. 1988 May;10(5):311-7.
It has been shown that calcium acetylhomotaurinate (Ca AOTA; Meram Patent, France) decreased voluntary ethanol intake in rats (1); this was antagonized by bicuculline. Homotaurine did not have this effect. We thought this was due to a different blood-brain barrier crossing ability for the two drugs. The present study was, therefore, planned to confirm blood-barrier crossing by Ca AOTA and to study the drug's physicochemical and pharmacokinetic characteristics. Both in vitro and in vivo (i.p.) administration of Ca AOTA increased the accumulation of [3H] GABA in rat striatal synaptosomal preparations. The chemical study confirmed Ca AOTA's great stability in biological and hydrophilic media, excluding a "homotaurine-dispensing" effect. The molecule was totally dissociated in such media, but the absence of any detectable acid form at any pH indicates that ion pairs are formed to cross barriers, and/or that a carrier system is used. The pharmacokinetic study showed short half-lives (5 and 30 min for the distribution and elimination phases) and small distribution volumes. However, the elimination phase distribution volume was dose-dependent, a further argument for a carrier transport system. From the present study it appears that Ca AOTA is an extremely stable drug, totally dissociated in hydrophilic media, which acts centrally as a GABA agonist after crossing the blood-brain barrier. It is not a precursor of homotaurine and presumably crosses barriers with the help of a transporter.
已表明乙酰高牛磺酸钙（Ca AOTA；法国梅拉姆专利）可降低大鼠的自愿乙醇摄入量（1）；荷包牡丹碱可拮抗此作用。高牛磺酸则无此作用。我们认为这是由于两种药物穿过血脑屏障的能力不同所致。因此，本研究旨在证实Ca AOTA可穿过血脑屏障，并研究该药物的理化和药代动力学特性。体外和体内（腹腔注射）给予Ca AOTA均可增加大鼠纹状体突触体制剂中[3H]GABA的蓄积。化学研究证实Ca AOTA在生物和亲水介质中具有很高的稳定性，排除了“释放高牛磺酸”的作用。该分子在这类介质中完全解离，但在任何pH值下均未检测到任何可检测的酸形式，这表明形成了离子对以穿过屏障，和/或使用了载体系统。药代动力学研究显示半衰期较短（分布和消除相分别为5分钟和30分钟）且分布容积较小。然而，消除相分布容积呈剂量依赖性，这进一步支持了载体转运系统的观点。从本研究看来，Ca AOTA是一种极其稳定的药物，在亲水介质中完全解离，穿过血脑屏障后在中枢起GABA激动剂的作用。它不是高牛磺酸的前体，推测借助转运体穿过屏障。
