GENTAMICIN IN THE YOUNG BEAGLE DOG: PHARMACOKINETICS, NEPHROTOXICITY AND BEHAVIOR IN A MODEL OF GLOMERULONEPHRITIS

JIM EDMOND RIVIERE, Purdue University

Abstract

Investigation of pharmacokinetics of certain drugs in experimental models of glomerulonephritis would facilitate development of protocols for computation of rational dose schedules for dogs with this disease. Eighteen healthy five month old beagles were used in this study. Gentamicin sulfate (10 mg/kg) was administered intravenously and blood samples were collected at selected times. Serum gentamicin concentrations were then determined using a radioimmunoassay procedure. The resulting concentration-time data were fitted to an open two-compartment pharmacokinetic model using nonlinear regression statistical programs on a digital computer. Similar pharmacokinetic studies were also conducted in dogs with experimentally induced glomerulonephritis. Polyvinyl alcohol toxicosis was found not to be a suitable model of glomerulonephritis because of the severity of the nonrenal lesions. Next an immune-mediated model was investigated. Canine glomerular basement membrane was extracted from normal beagle kidneys, purified and injected into rabbits. Anti-glomerular basement membrane antisera was then harvested and used to inoculate the young beagles. Nephrotoxic serum glomerulonephritis, evidenced by decreased creatinine clearance and characteristic light, immunofluorescent and electron microscopic lesions, was produced. This model was employed in investigating changes in drug pharmacokinetics in renal disease. The pharmacokinetic parameters of gentamicin in healthy, five month old beagles was similar to adult dogs except for a marginally increased volume of the central compartment. Cerebrospinal fluid concentration of gentamicin could only be considered significant when inflammation was present. The body clearance of gentamicin, derived from the two-compartment analysis, was equivalent to the twenty-four hour renal creatinine clearance indicating glomerular filtration was the primary route of renal drug elimination. The mean creatinine clearance was the same as that reported for adult dogs suggesting mature renal function in these animals. The disposition of gentamicin in acute glomerulonephritis was significantly changed from control values. The extrapolated initial serum concentration of drug and the elimination rate constant was decreased, but the body clearance and volume of distribution was increased. It was concluded that these parameters should be monitored in the patient with renal insufficiency for optimal prediction of drug serum concentrations. A single dose of gentamicin (15 mg/kg) given intravenously according to three different concentration-time profiles produced nephrotoxicity characterized by decreased renal function and formation, in the proximal tubule cytoplasm, of cytosomes with myeloid figures characteristic of gentamicin nephrotoxicity. In addition, single membrane limited vesicles containing granular proteinaceous material were seen in the proximal tubular cytoplasm of treated dogs. The relationship of the latter structure to the pathogenesis of gentamicin nephrotoxicity is not known. In general, the disposition of gentamicin in young beagles is comparable to adults. The changes in the pharmacokinetic parameters which occur in acute glomerulonephritis are noteworthy and not predicted by standard renal function tests. These changes necessitate collection of more complete pharmacokinetic data in patients with renal insufficiency if accurate dosage regimens are to be constructed. Finally, a single moderate dose of gentamicin can induce subclinical nephrotoxicity in healthy animals which could be clinically significant in patients with compromised renal function.

Degree

Ph.D.

Subject Area

Pharmacology

COinS