The renal excretion of gentamicin, an aminoglycoside antibiotic, was studied in the isolated perfused\nrat kidney (IPRK) model. Dose-linearity experiments were carried out at four doses (400,\n800, 1600, 3200 Ã?¼g), targeting initial perfusate levels of 5, 10, 20 and 40 Ã?¼g/ml. Additionally, gentamicin\nwas co-perfused with sodium bicarbonate (0.25 mM) and/or cimetidine (2 mM) to evaluate\nthe effect of urinary alkalization and secretory inhibition on gentamicin excretion and kidney\naccumulation. Gentamicin displayed net reabsorption in the IPRK, consistent with extensive\nluminal uptake. Kinetic analysis indicated that luminal transport of gentamicin (kidney ââ? â?? urine)\nis the rate-determining step for gentamicin urinary excretion. Clearance and cumulative excretion\ndecreased with increased gentamicin dose. Gentamicin kidney accumulation, estimated by mass\nbalance, ranged from ~20% - 30%. Urinary alkalization significantly increased gentamicin excretion,\nwith no effect on kidney accumulation. Conversely, cimetidine co-administration did not affect\ngentamicin clearance in the IPRK, but kidney accumulation was significantly reduced. When\nboth sodium bicarbonate and cimetidine were administered together, gentamicin kidney accumulation\ndecreased ~80% with corresponding increases in clearance and excretion ratio (XR)\ncompared to gentamicin alone. A main strategy to reduce the incidence of nephrotoxicity with\ngentamicin therapy (up to ~25%) involves reducing kidney accumulation of the compound. The\nresults of this research suggest that the combination of urinary alkalization and inhibition of basolateral\nsecretion (blood ââ? â?? kidney) may be a viable approach to mitigate aminoglycoside toxicity,\nand warrants further investigation.
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