GENTAMICIN INHIBITS CARRIER-MEDIATED DIPEPTIDE TRANSPORT IN KIDNEY

The effect of gentamicin on transport of pyroglutamylhistidine (pGlu-H is) was examined in rabbit renal brush-border membrane vesicles (BBMV) . Gentamicin, an aminoglycoside antibiotic, is limited in its usage be cause of nephrotoxicity characterized in part by transport defects in the proximal tubule. Since there is no information regarding the effec ts of gentamicin on renal peptide carriers, uptake of [H-3]pGlu-His wa s measured in BBMV following either in vivo or in vitro exposure to th e antibiotic. One hour after in vivo administration, the maximal rate (V-max) for pGlu-His transport was significantly reduced in isolated m embrane vesicles washed free of the drug, but the apparent Michaelis c onstant (K-m) was unaltered. Coincubation of membranes with gentamicin during measurements of pGlu-His uptake had a similar effect, causing a significant decrease in the V-max but not the K-m of transport. The addition of 5 mM magnesium to the uptake medium prevented the in vitro but not the in vivo effect. The data indicate that high doses of gent amicin inhibit the capacity but not the affinity of dipeptide transpor t in the kidney, prior to morphological changes which typify acute tub ular necrosis. The in vitro effect is rapid and involves a direct acti on of gentamicin on the brush-border membrane. The in vivo experiments show that toxicity may be prolonged and remains following removal of the drug from the renal brush border.