Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Lvshunkou District, Dalian, China.
Peptides. 2012 Feb;33(2):265-71. doi: 10.1016/j.peptides.2012.01.007. Epub 2012 Jan 18.
Bestatin, a dipeptide, a low molecular weight aminopeptidase inhibitor, has been demonstrated to be an immunomodulator with an antitumor activity. However, the transporter-mediated renal excretion of bestatin is not fully understood. The purpose of this study was to elucidate the transporter-mediated renal excretion mechanism for bestatin. The plasma concentration of bestatin was increased markedly and both the accumulative renal excretion and renal clearance of bestatin were decreased significantly after intravenous administration of bestatin in combination with probenecid. p-Aminohippuric acid (PAH), a substrate of organic anion transporter (OAT) 1, benzylpenicillin (PCG), a substrate of OAT3 and JBP485, a substrate of OAT1 and OAT3, reduced the uptake of bestatin in rat kidney slices and in hOAT1- or hOAT3-HEK 293 cells. The accumulation of bestatin in hOAT1-HEK and hOAT3-HEK 293 cells was significantly greater than that in vector-HEK, and the K(m) and V(max) were 0.679 ± 0.007 mM and 0.807 ± 0.006 nmol/mg protein/30s for OAT1, 0.632 ± 0.014 mM and 1.303 ± 0.015 nmol/mg protein/30s for OAT3 respectively. PAH and JBP485 inhibited significantly the uptake of bestatin in hOAT1-HEK with the K(i) values of 92 ± 9 μM and 197 ± 21 μM; and PCG, JBP485 inhibited significantly the uptake of bestatin in hOAT3-HEK 293 cells with the K(i) values of 88 ± 12 μM and 160 ± 16 μM. Our results are novel in demonstrating for the first time that OAT1 and OAT3 are involved in the renal excretion of bestatin.
贝他斯汀是一种二肽，一种低分子量的氨肽酶抑制剂，已被证明具有免疫调节作用和抗肿瘤活性。然而，贝他斯汀的经肾转运排泄机制尚未完全阐明。本研究旨在阐明贝他斯汀的经肾转运排泄机制。贝他斯汀与丙磺舒联合静脉给药后，贝他斯汀的血药浓度显著升高，累积肾排泄量和肾清除率均显著降低。对氨基马尿酸（PAH）是有机阴离子转运体（OAT）1 的底物，青霉素 G（PCG）是 OAT3 的底物，JBP485 是 OAT1 和 OAT3 的底物，这些物质均可减少大鼠肾切片和 hOAT1-或 hOAT3-HEK293 细胞对贝他斯汀的摄取。贝他斯汀在 hOAT1-HEK 和 hOAT3-HEK293 细胞中的积累明显大于载体-HEK，OAT1 的 K(m)和 V(max)分别为 0.679±0.007mM 和 0.807±0.006nmol/mg 蛋白/30s，OAT3 的 K(m)和 V(max)分别为 0.632±0.014mM 和 1.303±0.015nmol/mg 蛋白/30s。PAH 和 JBP485 可显著抑制 hOAT1-HEK 中贝他斯汀的摄取，K(i)值分别为 92±9μM 和 197±21μM；PCG 和 JBP485 可显著抑制 hOAT3-HEK293 细胞中贝他斯汀的摄取，K(i)值分别为 88±12μM 和 160±16μM。我们的研究结果首次表明，OAT1 和 OAT3 参与了贝他斯汀的肾排泄。
