Multiple pathways for fluoroquinolone secretion by human intestinal epithelial (Caco-2) cells

1 Human intestinal epithelial Caco-2 cells, T84 cells, and MDCKII cells transfected with human MDR1, were used to investigate the mechanistic basis of transintestinal fluoroquinolone secretion. 2 The fluoroquinolone grepafloxacin was secreted across Caco-2 monolayers by a saturable process (V-max = 16.9 +/- 3.4 n.mol.cm(-2).h(-1)). Net secretion was reduced by 2-deoxyglucose/azide treatment to reduce intracellular ATP. 3 Grepafloxacin inhibited [C-14]-ciprofloxacin (100 muM) secretion across Caco-2 monolayers (K-0.5 = 0.8 mM), and concurrently increased the cellular accumulation of ciprofloxacin from the basal medium, indicating inhibition of export across the apical membrane. 4 The unconjugated bile acid, cholic acid, was secreted across Caco-2 monolayers, and this secretion was sensitive to inhibition by the MRP-selective inhibitor MK-571, suggesting MRP2 involvement. Secretion of cholic acid (10 pm) across the apical membrane was also inhibited by grepafloxacin (K-0.5 = 0.3 mM), but not by ciprofloxacin. 5 In MDCKII-MDR1 monolayers, net secretion of grepafloxacin was increased by 3.5 fold compared with untransfected controls. Neither ciprofloxacin nor cholic acid showed net secretion in either MDCKII or MDCKII-MDR1 monolayers, showing that in contrast to grepafloxacin, neither are substrates for MDR1. 6 In T84 monolayers, which express MDR1 but not MRP2, neither ciprofloxacin nor cholic acid was secreted, whilst the V-max for grepafloxacin secretion was lower than in Caco-2 cells, which express both MDR1 and MRP2. 7 In conclusion, the transepithelial secretion of grepafloxacin is mediated by both MRP2 and MDR1, whereas ciprofloxacin is a substrate for neither. Grepafloxacin also competes for the ciprofloxacin-sensitive pathway, which remains to be elucidated. British Journal of Pharmacology (2002).