Urien S, Zini R, Lemaire M, Tillement J P
Laboratoire de Pharmacologie, Faculté de Médecine, Créteil, France.
J Pharmacol Exp Ther. 1990 Apr;253(1):305-9.
The interaction of cyclosporine A (cyclosporine) with human plasma lipoproteins has been investigated by combining in vitro and in vivo methods. Binding parameters were derived in vitro from an erythrocyte partitioning method, and provided reliable Ka (product of the number of binding sites by the association constant) estimates: high-density lipoprotein, 2.21 +/- 0.48; low-density lipoprotein, 1.23 +/- 0.12; and very low-density lipoprotein, 0.53 +/- 015 liters/g, showing that high-density lipoprotein was the major carrier of plasma cyclosporine. The effects of cyclosporine binding to lipoproteins were investigated in vivo by the intracarotid injection technique of Oldendorf in the rat. The brain extraction of cyclosporine was related inversely to the lipoprotein concentration in the injected solution, allowing estimation of nKa in vivo: high-density lipoprotein, 2.25 +/- 0.59; low-density lipoprotein, 0.62 +/- 0.13; and very low-density lipoprotein, 0.57 +/- 0.14 liters/g. This showed that brain uptake occurred from the free drug pool and possibly from a small part of the originally lipoprotein-bound pool of cyclosporine, at least for low-density lipoprotein-bound cyclosporine. These results allow the calculation of an index of the unbound plasma cyclosporine fraction.
通过结合体外和体内方法，对环孢素A（环孢素）与人血浆脂蛋白的相互作用进行了研究。结合参数是通过红细胞分配法在体外得出的，并提供了可靠的Ka（结合位点数量与缔合常数的乘积）估计值：高密度脂蛋白为2.21±0.48；低密度脂蛋白为1.23±0.12；极低密度脂蛋白为0.53±0.15升/克，表明高密度脂蛋白是血浆中环孢素的主要载体。通过大鼠体内奥尔德恩多夫颈内注射技术研究了环孢素与脂蛋白结合的影响。环孢素的脑摄取与注射溶液中的脂蛋白浓度呈负相关，从而可以在体内估计nKa：高密度脂蛋白为2.2±0.59；低密度脂蛋白为0.62±0.13；极低密度脂蛋白为0.57±0.14升/克。这表明脑摄取来自游离药物池，也可能来自环孢素最初与脂蛋白结合的一小部分池，至少对于与低密度脂蛋白结合的环孢素是如此。这些结果使得能够计算未结合血浆中环孢素部分的指数。
