Sodium and pH dependent carrier-mediated transport of antibiotic, fosfomycin, in the rat intestinal brush-border membrane.
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 Kt = 15.3 mM and Jmax = 7.78 nmol/30 s/mg protein at 37 degrees C. An overshoot uptake of FOM was observed in the presence of an inwardly direct Na+ gradient. The replacement of extravesicular Na+ with choline or mannitol significantly reduced the uptake. An addition of a protonophore, FCCP, significantly decreased the initial uptake of FOM in the absence of Na+ gradient but in the presence of a H+ gradient (pHin = 7.5, pHout = 6.0), whereas in the absence of a H+ gradient no significant difference was observed between the uptakes at an acidic pH (pHin = pHout = 6.0) and a neutral pH (pHin = pHout = 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 phosphate 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.
Ishizawa
T
T
Faculty of Pharmaceutical Sciences, Kanazawa University, Japan.
Tsuji
A
A
Tamai
I
I
Terasaki
T
T
Hosoi
K
K
Fukatsu
S
S
D000818:Animals; D001692:Biological Transport; D005110:Extracellular Space / Q000378:metabolism; D005578:Fosfomycin / Q000493:pharmacokinetics*; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D008566:Membranes / Q000378:metabolism; D008871:Microvilli / Q000378:metabolism* / Q000648:ultrastructure; D009994:Osmolar Concentration; D010710:Phosphates / Q000378:metabolism; D011188:Potassium / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D012964:Sodium / Q000378:metabolism* / Q000502:physiology; D013696:Temperature; D013997:Time Factors
D010710:Phosphates; D005578:Fosfomycin; D012964:Sodium; D011188:Potassium