Han Y H, Kato Y, Sugiyama Y
Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan.
J Pharmacol Exp Ther. 1999 Oct;291(1):204-12.
The excretion and tissue distribution kinetics of a novel antifolate, MX-68, were evaluated under conditions of a continuous steady-state infusion in Sprague-Dawley rats (SDRs). The biliary excretion clearance defined with respect to the hepatic concentration (CL(bile, h)) was much lower in Eisai hyperbilirubinemic rats with a hereditary deficiency in canalicular multispecific organic anion transporter than that in SDRs, suggesting the involvement of canalicular multispecific organic anion transporter in its transport across the bile canalicular membrane. The CL(bile, h) in SDRs increased as the infusion rate increased; this can be largely explained by saturation of the intracellular binding of MX-68. On the other hand, the urinary excretion clearance defined with respect to the renal concentration (CL(urine, k)) was comparable for the two strains but showed an increase and subsequent decrease as the renal concentration increased. This nonlinear profile was also found even when the CL(urine, k) was normalized by the unbound fraction in kidney. Therefore, this kinetic profile represents the saturation of both reabsorption and secretion. Reabsorption of MX-68 in kidney was supported by its saturable transport by renal brush border membrane vesicles at an inward H(+) gradient. The liver-to-plasma unbound concentration ratio decreased as the steady-state plasma concentration increased, suggesting that MX-68 is taken up by a saturable mechanism or mechanisms. Thus, the saturation of transport systems across several plasma membranes and intracellular binding in both the liver and kidney produce the nonlinear disposition of MX-68.
在对斯普拉格-道利大鼠（SDRs）进行连续稳态输注的条件下，评估了一种新型抗叶酸药物MX-68的排泄和组织分布动力学。在遗传性胆小管多特异性有机阴离子转运体缺乏的卫材高胆红素血症大鼠中，相对于肝脏浓度定义的胆汁排泄清除率（CL(bile, h)）远低于SDRs，这表明胆小管多特异性有机阴离子转运体参与了其跨胆小管膜的转运。SDRs中的CL(bile, h)随着输注速率的增加而增加；这在很大程度上可以通过MX-68细胞内结合的饱和来解释。另一方面，相对于肾脏浓度定义的尿液排泄清除率（CL(urine, k)）在两个品系中相当，但随着肾脏浓度的增加呈现先增加后降低的趋势。即使CL(urine, k)通过肾脏中的未结合分数进行归一化，也发现了这种非线性特征。因此，这种动力学特征代表了重吸收和分泌的饱和。MX-68在肾脏中的重吸收得到了其在向内的H(+)梯度下由肾刷状缘膜囊泡进行的可饱和转运的支持。肝脏与血浆的未结合浓度比随着稳态血浆浓度的增加而降低，这表明MX-68是通过一种或多种可饱和机制被摄取的。因此，跨多个质膜的转运系统以及肝脏和肾脏中细胞内结合的饱和导致了MX-68的非线性处置。
