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Dose-response studies of gentamicin nephrotoxicity in rats with experimental renal dysfunction. I. Subtotal surgical
Abstract:
Gentamicin pharmacokinetics and nephrotoxicity have not been widely studied in animals with preexisting renal dysfunction, despite the fact that nephrotoxicity is a continuing manifestation of clinical therapy. The present study contrasted the dose-response nephrotoxicity of gentamicin in control rats with that of rats with renal insufficiency secondary to subtotal (2/3) surgical nephrectomy. Total daily doses ranging from 0 to 120 mg/kg were given in a divided regimen, every 8 hr and doses were reduced by doubling the interval in subtotally nephrectomized (Nx) rats, in proportion to impaired renal elimination on the first day of gentamicin administration. Estimates of renal function, including creatinine clearance, fractional sodium and potassium excretion, and serum creatinine and urea nitrogen, were collected after 6 and 12 days of dosing. In addition, urinary N-acetyl-beta-D-glucosaminidase excretion (6 days), in vitro renal cortical slice accumulation of tetraethylammonium (TEA) (6 days), quantified morphological lesions (12 days), and renal gentamicin concentrations (6 days) were examined. Pharmacokinetic data collected immediately after the first dose revealed a reduced gentamicin clearance and slightly reduced volume of distribution, with a corresponding prolonged half-life in the Nx rats. Based on statistical analysis of the dose-response relationships, Nx rats were functionally resistant to gentamicin nephrotoxicity after 6 days of dosing. This resistance was partially reversed by 12 days dosing, despite light-microscopic evidence of greater structural damage in the control rats. Renal parenchymal gentamicin concentrations were lower at some doses in the Nx rats, in contrast to the higher fractional reabsorption found in these rats at all doses. TEA transport was depressed at all doses in control rats but not at the lower doses in Nx rats, indicating that resistance was partially mediated at the level of the proximal tubular epithelium. This study demonstrates altered gentamicin pharmacokinetics and nephrotoxicity in a surgical model of renal dysfunction in rats.
Insights
Rats with reduced kidney function showed resistance to gentamicin nephrotoxicity initially. This resistance decreased over time, even with less structural damage observed in these animals compared to controls.
Area of Science:
- Pharmacology
- Nephrology
- Toxicology
Background:
- Gentamicin nephrotoxicity is a significant clinical concern, yet poorly understood in patients with pre-existing renal impairment.
- Limited research exists on how compromised kidney function affects gentamicin's pharmacokinetic profile and toxicity.
Purpose of the Study:
- To investigate the dose-response relationship of gentamicin-induced nephrotoxicity in rats with surgically induced renal insufficiency.
- To compare gentamicin pharmacokinetics and renal toxicity between control rats and rats with subtotal nephrectomy (Nx).
Main Methods:
- Rats underwent subtotal (2/3) surgical nephrectomy to model renal insufficiency.
- Both control and Nx rats received varying daily doses of gentamicin (0-120 mg/kg) every 8 hours.
- Renal function, gentamicin accumulation, urinary markers, and morphological damage were assessed after 6 and 12 days.
Main Results:
- Nephrectomized rats exhibited altered gentamicin pharmacokinetics, including reduced clearance and a prolonged half-life.
- Nx rats demonstrated functional resistance to gentamicin nephrotoxicity at 6 days, which partially reversed by 12 days.
- Proximal tubular dysfunction, indicated by impaired tetraethylammonium (TEA) transport, was less pronounced in Nx rats at lower doses.
Conclusions:
- Surgical renal insufficiency in rats alters gentamicin pharmacokinetics and confers initial resistance to nephrotoxicity.
- This resistance appears partially mediated at the proximal tubular level, suggesting a complex interaction between renal function and drug toxicity.
- Findings highlight the need for careful consideration of gentamicin dosing and monitoring in renally impaired patients.