Scientific Basis of Drug Disposition in the Kidney and its Application to Clinical Dosage Regimens.

肾脏是外源性药物排泄的主要器官，在药物代谢动力学中具有重要作用。在本研究中，我们研究了阴离子，阳离子，两性和非离子药物转运系统的结构和调节机制，利用肾质膜囊泡，培养的肾上皮细胞，和离体灌流肾。此外，我们还开发了利用药物在肾脏中分布的基本信息设计临床给药方案的新策略.利用大鼠离体灌流肾，我们证明了基底外侧膜转运是肾小管分泌物中对氨基马尿酸跨上皮转运的决定性步骤.肾上皮细胞株LLC-PK_1可通过有机阳离子转运系统转运普鲁卡因胺，普鲁卡因胺在细胞单层内由基底侧向顶侧单向转运。此外，我们还证实了肾有机阳离子转运蛋白在非洲爪蟾卵母细胞中的表达，并且一个1.4-2.4 kb的poly（A）^+ RNA片段表达了该转运蛋白.人P-糖蛋白在猪肾上皮细胞株LLC-PK_1的顶膜上表达。地高辛通过人P-糖蛋白转运，这是一种以前未发现的肾脏药物转运系统。通过群体药代动力学方法分析来自常规患者护理的治疗药物监测数据。影响药物处置的协变量可通过临床试验数据进行评价。我们证明了基于群体药代动力学参数的贝叶斯推断方法对于个体患者的剂量调整是有用的。

The kidney is a major organ for the excretion of xenobiotics, and is of critical importance in the pharmacokinetics. In the present study, we examined the structure and the regulatory mechanisms of the anionic, cationic, amphoteric and nonionic drug transport system, utilizing the renal plasma membrane vesicles, the cultured kidney epithelial cell, and the isolated perfused kidney. In addition, we developed the new strategy to design clinical dosage regimens by use of the basic information on the drug disposition in the kidney.1. Utilizing the rat isolated perfused kidney, we demonstrate that the basolateral membrane transport is a determining step in transepithelial transport of p-aminohippurate in renal tubular secretion.2. The kidney epithelial cell line LLC-PK_1 can transport procainamide by the organic cation transport system, and procainamide in transported unidirectionally from basolateral to apical side across the cell monolayer. In addition, we demonstrated that the renal organic cation transporter was expressed in Xenopus leavis oocytes and that a 1.4-2.4 kb poly(A)^+ RNA fragment expressed the transporter.3. Human P-glycoprotein was expressed on the apical membrane of porcine kidney epithelial cell line, LLC-PK_1. Digoxin is transported by human P-glycoprotein, which is a previously undiscovered drug transport system in the kidney.4. Therapeutic drug monitoring data from the routine patient care were analyzed by the population pharmacokinetic approach. The covariates influencing the drug disposition could be evaluated by the clinical test data. We demonstrated the Bayesian inference method based on the population pharmacokinetic parameters is useful for the dose-adjustment in individual patients.