Machard B, Misslin P, Lemaire M
Biopharmaceutical Department, Sandoz Ltd., Basle, Switzerland.
J Pharm Pharmacol. 1989 Oct;41(10):700-4. doi: 10.1111/j.2042-7158.1989.tb06344.x.
The intracarotid injection technique has been used to determine the unidirectional brain uptake of an antifungal, lipophilic agent, terbinafine (Lamisil, Sandoz Basle), in the rat. Ultrafiltration showed it to be highly bound to human plasma, human serum albumin (HSA), alpha 1-acid glycoprotein (AAG) and lipoproteins (VLDL, LDL, HDL). The effect of plasma protein binding of the drug on brain uptake was also examined with the technique. The lowest brain uptake was observed in the presence of plasma (6%); it varied from 23 to 30% with physiological concentrations of VLDL, LDL and HSA and was significantly higher (43-45%) in the presence of physiological concentrations of AAG and HDL. The free fraction as determined in-vitro and the brain uptake of the drug varied inversely with the plasma protein concentrations; however, the brain uptake was higher than expected from in-vitro measurements. These data indicate that the amount of circulating Lamisil available for brain penetration exceeds its free fraction; they also show that plasma proteins differently reduce the brain transport of the drug.
已采用颈内注射技术来测定大鼠体内一种抗真菌亲脂性药物特比萘芬（兰美抒，山德士公司，巴塞尔）的单向脑摄取量。超滤显示它与人体血浆、人血清白蛋白（HSA）、α1-酸性糖蛋白（AAG）和脂蛋白（极低密度脂蛋白、低密度脂蛋白、高密度脂蛋白）高度结合。还使用该技术研究了药物的血浆蛋白结合对脑摄取的影响。在有血浆存在的情况下观察到最低的脑摄取量（6%）；在生理浓度的极低密度脂蛋白、低密度脂蛋白和人血清白蛋白存在时，脑摄取量在23%至30%之间变化，而在生理浓度的α1-酸性糖蛋白和高密度脂蛋白存在时显著更高（43% - 45%）。体外测定的游离分数与药物的脑摄取量呈负相关；然而，脑摄取量高于体外测量预期的值。这些数据表明可用于脑渗透的循环兰美抒量超过其游离分数；它们还表明血浆蛋白对药物脑转运的降低程度不同。
