Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
Eur J Pharm Sci. 2013 Jan 23;48(1-2):351-9. doi: 10.1016/j.ejps.2012.11.008. Epub 2012 Nov 29.
The aim of this study was to investigate the pharmacokinetic mechanism of interaction between JBP485 and 1α,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)]. Rats were injected intraperitoneally with 0.64 nmol/kg/day 1,25(OH)(2)D(3) in 1 ml/kg corn oil for 5 days. The plasma and urine concentrations of JBP485 after intravenous administration and the uptake of JBP485 in kidney slices in vitro were determined by liquid chromatography/tandem mass spectrometry. Quantitative polymerase chain reaction, western blotting, immunohistochemical analysis and immunofluorescence were used to determine the changes in the expression of organic anion transporter (Oat)1 and Oat3 in rat kidney in response to 1,25(OH)(2)D(3) treatment. The plasma concentrations and AUCs of JBP485 were significantly increased, while the renal clearance of JBP485 and uptake of JBP485 in kidney slices were significantly decreased after 1,25(OH)(2)D(3) treatment. These results confirmed that 1,25(OH)(2)D(3) inhibited renal excretion of JBP485. Moreover, 1,25(OH)(2)D(3) decreased expression of Oat1 and Oat3 in rat kidney. Our results are novel in demonstrating an interaction between JBP485 and 1,25(OH)(2)D(3) when they are co-administered. The mechanism of interaction between JBP485 and 1,25(OH)(2)D(3) could be explained at least in part by inhibitory effect of 1,25(OH)(2)D(3) on expression of Oats in rat kidney.
本研究旨在探讨 JBP485 与 1α,25-二羟基维生素 D(3)[1,25(OH)(2)D(3)]相互作用的药代动力学机制。将大鼠以 0.64nmol/kg/天的剂量用 1ml/kg 玉米油中的 1,25(OH)(2)D(3) 经腹腔注射，连续 5 天。采用液相色谱/串联质谱法测定大鼠静脉注射 JBP485 后血浆和尿液中的浓度以及体外肾切片中 JBP485 的摄取情况。通过定量聚合酶链反应、蛋白质印迹法、免疫组织化学分析和免疫荧光法检测大鼠肾脏中有机阴离子转运体(Oat)1 和 Oat3 对 1,25(OH)(2)D(3)处理的反应的表达变化。结果表明，1,25(OH)(2)D(3)处理后，JBP485 的血浆浓度和 AUC 显著增加，而 JBP485 的肾清除率和肾切片摄取率显著降低。这些结果证实 1,25(OH)(2)D(3)抑制了 JBP485 的肾脏排泄。此外，1,25(OH)(2)D(3)降低了大鼠肾脏中 Oat1 和 Oat3 的表达。本研究结果表明，当 JBP485 与 1,25(OH)(2)D(3)合用时，两者之间存在相互作用，这在以前的研究中尚未报道过。JBP485 与 1,25(OH)(2)D(3) 相互作用的机制至少部分可以用 1,25(OH)(2)D(3) 抑制大鼠肾脏 Oats 表达来解释。
