Sodium and pH Dependent Carrier-Mediated Transport of Antibiotic, Fosfomycin, in the Rat Intestinal Brush-Border Membrane

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The mechanism of intestinal absorption of an antimicrobial agent, fosfomycin (FOM), was investigated in rats using small intestinal brush-border membrane vesicles (BBMV). The uptake of [³H]FOM by BBMV was osmolarity- and temperature-sensitive and showed apparently saturable uptake kinetics consistent with the Michaelis-Menten equation, having K_t=15.3 mM and J_max=7.78 nmol/30 s/mg protein at 37°C. An overshoot uptake of FOM was observed in the presence of an inwardly directed Na⁺ gradient. The replacement of extravesicular Na⁺ with choline or mannitol significantly reduced the uptake. An addition of a protonophore, FCCP, significantly decreased the intial uptake of FOM in the absence of Na⁺ gradient but in the presence of a H⁺ gradient (pH_in=7.5, pH_out=6.0), whereas in the absence of a H⁺ gradient no significant difference was observed between the uptakes at an acidic pH (pH_in=pH_out=6.0) and a neutral pH (pH_in=pH<out>=7.5). An inside negative potassium diffusion potential induced by valinomycin enhanced significantly the uptake of FOM. The uptake of FOM in the presence of both Na⁺- and H⁺- gradients was significantly inhibited by phosphate, arsenate and phosphonoformic acid (PFA), which are specific inhibitors of phoshate transport, but not by D-glucose. Based on these results, it is concluded that FOM transport in the small intestine is partially shared with the Na⁺-phosphate cotransport system and in part occurs via a H⁺- gradient dependent carrier-mediated system.