Kinetics of Rena1 Dispositon and Pharmacological Effect of Peptides

近年来各种生物活性多肽的发现促使其应用于疾病的治疗，肾脏被认为是调节多肽药物处置的重要器官。在本研究中，我们研究了心房钠肽（ANP）、脑钠肽（BNP）和粒细胞集落刺激因子（GCSF）在大鼠肾内的分布，并动力学分析了这些肽的药理作用。大鼠肾脏离体灌注研究表明，肾内GCSF的主要消除途径是肾小球滤过，滤过的GCSF可通过饱和过程从管腔侧转移到肾组织中。asialo-GCSF的滤过率和肾分布大于didialo - gcsf和monosialo-GCSF。与GCSF相比，GCSF与聚戊二烯-共马来酸结合物能够从肾小球滤过中逃脱，并在大鼠静脉给药后显示出更高的中性粒细胞增殖活性。群体分析可以量化ANP和BNP的净利尿活性，也可以评估血流动力学变化和中性内多肽酶抑制剂的影响。利用可透性支架上培养的lc - pk_1细胞单层膜，在肾上皮细胞的顶膜和底外侧膜上均存在利钠肽受体。

Recent discovery of various bioactive peptides prompted their application to the treatment of dlseases, and the kidney is recognized as an important organ to regulate the disposition of peptide drugs. In the present study, we have investigated the renal disposition of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and granulocyte-colony stimulating factor (GCSF) in rats, and kinetically analyzed the pharmacologic effect of peptides.1. The isolated perfusion study of rat kidney has shown that the major elimination route of GCSF in the kidney is the glomerular filtration and the filtrated GCSF could be transferred into the renal tissue from the luminal side by the saturable process.2. The filtration fraction and the renal distribution of asialo-GCSF were greater than those of disialo- and monosialo-GCSF.A GCSF conjugate with poly-(stirene-co-maleic acid) was able to escape from glomerular filtration and showed a higher neutrophil-proliferating activity- after i.v.administration to rats compared to GCSF.3. The population analysis enabled quantification of net diuretic activities of ANP and BNP, and also assessment of the effects of hemodynamic change and an inhibitor of neutral endopeptidase.4. Utilizing LLC-PK_1 cell monolayrs cultured on permeable supports, the presence of natriuretic peptide receptors was indicated in both the apical and basolateral membranes in the kidney epithelial cells.