Kelmer-Bracht A M, Ishii-Iwamoto E L, Bracht A
Laboratory of Liver Metabolism, University of Maringá, Brazil.
Biochem Pharmacol. 1993 May 5;45(9):1863-71. doi: 10.1016/0006-2952(93)90445-3.
Transport and distribution space of niflumic acid in the perfused rat liver were investigated employing the multiple-indicator dilution technique with constant infusion of the drug (step input). Niflumic acid permeated the cell membrane in both directions at very high rates and its distribution in the cellular space was flow-limited; at least at 37 degrees, the rates of influx and efflux could not be measured. Dissociation of the niflumic acid-albumin complex also occurred at very high rates. The apparent space of distribution of niflumic acid in the liver depended on the concentration of the drug and varied between 4.37 (1 mM) and 43.5 (10 microM) times the water space; even with 90% extracellular binding to albumin, the apparent space of distribution of niflumic acid was 5.1 times greater than the water space. The high apparent spaces of distribution reflected the high intracellular concentrations. The ratio of intracellular bound plus free concentration to the extracellular bound plus free concentration (Ci/Ce) varied between 6.62 (1 mM portal niflumic acid) and 71.0 (10 microM portal niflumic acid). Metabolic transformation depended on the concentration of the free form. Intracellular binding is probably the major reason for the high concentration of the drug in the hepatic tissue.
采用多指示剂稀释技术并持续输注药物（阶跃输入），研究了灌注大鼠肝脏中尼氟酸的转运和分布空间。尼氟酸以非常高的速率双向透过细胞膜，其在细胞内空间的分布受血流限制；至少在37℃时，无法测量其流入和流出速率。尼氟酸 - 白蛋白复合物的解离也以非常高的速率发生。尼氟酸在肝脏中的表观分布空间取决于药物浓度，在水空间的4.37倍（1 mM）至43.5倍（10 microM）之间变化；即使90%在细胞外与白蛋白结合，尼氟酸的表观分布空间仍比水空间大5.1倍。高表观分布空间反映了高细胞内浓度。细胞内结合加游离浓度与细胞外结合加游离浓度的比值（Ci/Ce）在6.62（1 mM门静脉尼氟酸）至71.0（10 microM门静脉尼氟酸）之间变化。代谢转化取决于游离形式的浓度。细胞内结合可能是肝组织中药物浓度高的主要原因。
