Transporter-Mediated Hepatic Uptake of Ulifloxacin, an Active Metabolite of a Prodrug-Type New Quinolone Antibiotic Prulifloxacin, in Rats

Abstract

Prulifloxacin (PUFX) is a prodrug-type new quinolone antibiotic and immediately converted to an active metabolite, ulifloxacin (UFX). It has been previously reported that UFX is highly excreted into the bile, although the hepatic uptake process of UFX has not been investigated yet. In this study, we attempted to characterize the mechanism of hepatic uptake of UFX in rats. The hepatic uptake in vivo was evaluated by integration plot analysis. Furthermore, the uptake of [(14)C]-UFX by isolated rat hepatocytes was measured, and the effects of several transporter inhibitors and other quinolone antibiotics on the uptake were examined. The hepatic uptake clearance of UFX (1 mg/kg) was calculated to be 37.7 mL/min/kg, which was larger than those at doses of 5 and 25 mg/kg and was decreased by co-administration of cyclosporine A (CysA; 30 mg/kg). The uptake of [(14)C]-UFX by isolated rat hepatocytes linearly increased up to 1 min and also inhibited by CysA. Other quinolone antibiotics inhibited the [(14)C]-UFX uptake in a concentration-dependent manner, whereas taurocholate and estrone-3-sulfate partially inhibited the [(14)C]-UFX uptake. These results demonstrate that a carrier-mediated transport system which is common to the quinolone antibiotics is involved in the uptake of UFX in the rat liver.

Effects of Grepafloxacin on the Function of Human Polymorphonuclear Leukocytes and the Phosphorylation of p38 Mitogen-Activated Protein Kinase

“…PUFX is a fluoroquinolone that has strong bactericidal activity and is rapidly incorporated into PMNs, being similar to GPFX. However, its effects on signal transduction are still unknown [13][14][15] . In this study, PUFX neither affected fMLP-stimulated chemotaxis or ROS production in PMN nor the phosphorylation of p38 or p42 (ERK2) MAPK in PMN in vitro.…”

“…PUFX is quickly converted to an active metabolite, ulifloxacin (UFX), after absorption. However, the immunomodulatory effects of PUFX and UFX on PMNs have not been reported [13][14][15] . On the other hand, studies using specific inhibitors of protein kinases revealed that p38 and p42 (ERK2) mitogen-activated protein kinase (MAPK) participated in both signaling pathways of NADPH oxidase activation (O 2 -production) [16][17][18] , phagocytosis and chemotaxis [19] of PMNs.…”

Active Uptake of Ulifloxacin from Plasma to Lung That Controls Its Concentration in Epithelial Lining Fluid

“…It shows reasonable efficacy against infections in various organs including the lung. 14) We previously showed that penetration of ulifloxacin into the rat ELF might be induced by a certain active transport. 15) The transport system has, however, not been clarified yet.…”