Inhibitory effect of 1α,25-dihydroxyvitamin D₃ on excretion of JBP485 via organic anion transporters in rats

Abstract

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.