Renal tubular transport of gentamicin in the rat

Abstract

The renal handling of gentamicin in the rat was examined by clearance, microinjection, and renal cortical-slice techniques. The steady-state renal clearance of 14C-gentamicin, when corrected for the 7.5% binding to plasma protein, was not significantly different from that of 3H-inulin. At the end of the renal clearance experiments, the cortical concentration of gentamicin was 93 +/- 7 microgram/g of tissue (N = 7), a concentration threefold greater than that of the medulla and 20-fold greater than that of serum. Absorption of 3H-gentamicin along the proximal convoluted tubule and loop of Henle was demonstrated by the tubular microinjection technique. No reabsorption of 3H-gentamicin was detected beyond the early distal convoluted tubule. The tubular absorption of 3H-gentamicin was load dependent. Fractional absorption of 3H-gentamicin averaged 30.1 +/- 2.7% when the dose of 3H-gentamicin injected into early proximal tubular convolutions averaged 132 +/- 17 pg. It was decreased to 13.6 +/- 2.6% when the microinjected dose of gentamicin was increased to 1996 +/- 388 pg. No evidence of transtubular absorption of 3H-gentamicin was detected during the microinjection experiments. Microperfusion of pertubular capillaries failed to demonstrate urinary precession of 3H-gentamicin over 14C-inulin, a finding which argues against a rapid transtubular secretory flux of gentamicin. Significant uptake of gentamicin was demonstrated by renal cortical slices incubated in medium containing 14C-gentamicin. The accumulation of 14C-gentamicin by renal cortical slices was not inhibited by probenecid or N1-methylnicotinamide but was inhibited by netilmicin and tobramycin. These data support the conclusion that the renal accumulation of gentamicin reflects transport of gentamicin across both the apical and basolateral membranes of proximal tubular epithelium.

Decreased Expression of Na+/K+-ATPase, NHE3, NBC1, AQP1 and OAT in Gentamicin-induced Nephropathy

“…However, gentamicin may cause a dose-dependent nephrotoxicity (Bennett, 1997). Previous studies have shown that gentamicin is mainly concentrated in the proximal tubular cells, and the resultant renal dysfunction may be recognized as Fanconi-like syndrome of a proximal tubular damage (Pastoriza-Munoz et al, 1979;Gainza et al, 1997).…”

Correlation between renal membrane binding and nephrotoxicity of aminoglycosides

“…The nephrotoxicity of these drugs is associated with selective accumulation of aminoglycosides in the kidney, with cortical levels reaching as high as 20 times the circulating levels in serum (10,40). Aminoglycosides are known to accumulate in renal tissue via tubular reabsorption as well as by extraction from the circulation at the basolateral surface of the kidney, although brush border uptake is thought to contribute more on a quantitative basis (6,7,17,34). However, it remains to be established whether the nephrotoxicity is a consequence of accumulated drug or relates to an interaction at the initial point of contact between the renal cell and the aminoglycoside, the plasma membrane.…”

Dietary composition alters gentamicin-induced nephrotoxicity in rats

“…membrane (pasturiza-Munoze et al, 1979). DnJg accumulation into lysosomes can be demonstrated by autoradiography (Silverblatt and Kuehn, 1979) or by Immunogold labeling (Beauchamp et a/., 1991) and may reach concentrations that are several-fold higher than the nonnal serum levels (Giuliano et al, 1984).…”