DOI: http://dx.doi.org/10.18203/2319-2003.ijbcp20150374

Pharmacokinetics and clinical evaluations of gentamicin-induced nephrotoxicity in puppies

Fidelis A. Gberindyer, Temidayo O. Omobowale, Matthew O. Abatan

Abstract


Background: The study was aimed at investigating the effect of dosing intervals on gentamicin nephrotoxicity in puppies.

Methods: Local puppies were assigned to Groups A and B (n=6) and administered gentamicin intramuscularly once (6 mg/kg) or twice (3 mg/kg) daily, respectively, for 5 consecutive days. Biochemical parameters such as urine protein, creatinine, ɤ-glutamyl transferase, as well as serum creatinine (SCR) and urea nitrogen were determined spectrophotometrically using specific kits before and after treatment. Peak and trough serum concentrations of gentamicin were determined by immunoassay on 1st and 5th day treatment. Thereafter, elimination rate constants and corresponding half-lives were calculated.

Results: No significant increase in SCR concentrations in both groups was observed, but values on day 7 were slightly above normal. Conversely, there was a significant increase above normal in serum urea nitrogen on days 4 and 7 in Group A, whereas this was observed only on day 7 in Group B. Even though all other biochemical parameters assayed for were within normal, an increasing trend was noticed as the length of treatment days increased in both groups. In both groups, peak serum concentrations of gentamicin did not differ significantly. There was a 4- and 16-fold significant increase in trough levels after the last treatment in Groups A and B, respectively. Although peak and trough concentrations increased with increasing length of treatment, all the values were well below 10 µg/ml and 2 µg/ml, respectively, as required.

Conclusion: These suggest the risk of nephrotoxicity following treatment with gentamicin beyond 5 consecutive days irrespective of the dosing interval in puppies.


Keywords


Gentamicin, Nephrotoxicity, Dosing interval, Puppies

Full Text:

PDF

References


Tarloff JB, Lash LH. In: H M, PM, editors. Toxicology of the Kidney: antibiotic-Induced Nephrotoxicity. 3rd Edition., Ch. 16 New York: CRC Press; 2005: 635-85.

Krastev SV. Gentamicin disposition in cerebrospinal fluid (CSF) and aqueous humour in healthy dogs. Trak J Sci. 2008;6 Suppl 1:14-8.

Edson RS, Terrell CL. The aminoglycosides. Mayo Clin Pract. 1999;74(5):519-28.

Aliu YO. Veterinary Pharmacology. Zaria: Tamaza Publishing Co.; 2011:48-9.

Moore RD, Smith CR, Lietman PS. The association of aminoglycoside plasma levels with mortality in patients with gram-negative bacteremia. J Infect Dis. 1984;149(3):443-8.

Laurent G, Kishore BK, Tulkens PM. Aminoglycoside-induced renal phospholipidosis and nephrotoxicity. Biochem Pharmacol. 1990;40(11):2383-92.

Barclay ML, Begg EJ. Aminoglycoside toxicity and relation to dose regimen. Adverse Drug React Toxicol Rev. 1994;13(4):207-34.

Lortholary O, Tod M, Cohen Y, Petitjean O. Aminoglycosides. Med Clin North Am. 1995;79(4):761-87.

Kumin GD. Clinical nephrotoxicity of tobramycin and gentamicin. A prospective study. JAMA. 1980;244(16):1808-10.

Belknap S. Aminoglycoside antibiotics. In: Craig CR, Stitzel RE, editors. Modern Pharmacology with Clinical Applications. Boston: Brown and Company; 1997: 573-4.

Kahn CM. The Merck Veterinary Manual. 10th Edition. New Jersey: Merck and Co.; 2010.

Riviere JE, Coppoc GL, Hinsman EJ, Carlton WW, Traver DS. Species dependent gentamicin pharmacokinetics and nephrotoxicity in the young horse. Fundam Appl Toxicol. 1983;3(5):448-57.

Sojka JE, Brown SA. Pharmacokinetic adjustment of gentamicin dosing in horses with sepsis. J Am Vet Med Assoc. 1986;189(7):784-9.

Gilbadi M, Perrier D. Pharmcokinetics. New York: Marcel Dekker Inc.; 1982.

Coca SG, Parikh CR. Urinary biomarkers for acute kidney injury: perspectives on translation. Clin J Am Soc Nephrol. 2008;3(2):481-90.

Rouse R, Siwy J, Mullen W, Mischak H, Metzger J, Hanig J. Proteomic candidate biomarkers of drug-induced nephrotoxicity in the rat. PLoS One. 2012;7(4):e34606.

Duncan JR, Prasse KW, Mahaffey EA. Veterinary Laboratory Medicine: clinical Pathology. 3rd Edition., Ch. 9. Ames: Iowa State University Press; 1994: 1-182.

Lees GE, Brown SA, Elliott J, Grauer GE, Vaden SL. American College of Veterinary Internal Medicine. Assessment and management of proteinuria in dogs and cats: 2004 ACVIM forum consensus statement (small animal). J Vet Intern Med. 2005;19(3):377-85.

Stockham SL, Scott MA. Urinary system. In: SL MA, Ames IA, editors Fundamentals of Veterinary Clinical Pathology. 2nd Edition. Oxford: Blackwell Publishing; 2008: 479.

Ward JP. Gamma-glutamyl transpeptidase. A sensitive indicator of renal ischaemic injury in experimental animals and renal homograft rejection in man. Ann R Coll Surg Engl. 1975;57(5):248-61.

Adelman RD, Conzelman G, Spangler W, Ishizaki G. Comparative nephrotoxicity of gentamicin and netilmicin: functional and morphological correlations with urinary enzymes. In: Dubach UL, Schmidt U, editors. Diagnostic Significance of Enzymes and Protein in Urine. Bern: Hans Huber; 1979: 166-82.

Greco DS, Turnwald GH, Adams R, Gossett KA, Kearney M, Casey H. Urinary gamma-glutamyl transpeptidase activity in dogs with gentamicin-induced nephrotoxicity. Am J Vet Res. 1985;46(11):2332-5.

Grauer GF, Greco DS, Behrend EN, Mani I, Fettman MJ, Allen TA. Estimation of quantitative enzymuria in dogs with gentamicin-induced nephrotoxicosis using urine enzyme/creatinine ratios from spot urine samples. J Vet Intern Med. 1995;9(5):324-7.

Rivers BJ, Walter PA, O’Brien TD, King VL, Polzin DJ. Evaluation of urine gamma-glutamyl transpeptidase-to-creatinine ratio as a diagnostic tool in an experimental model of aminoglycoside-induced acute renal failure in the dog. J Am Anim Hosp Assoc. 1996;32(4):323-36.

McEvoy GK, Miller JA, Snow EK, Welsh OH. AHFS Drug Information. Bethesda, MD: American Society of Health-System Pharmacist Inc.; 2002: 66-7.

Prins JM, Büller HR, Kuijper EJ, Tange RA, Speelman P. Once versus thrice daily gentamicin in patients with serious infections. Lancet. 1993;341(8841):335-9.

Moore RD, Lietman PS, Smith CR. Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis. 1987;155(1):93-9.

Jernigan AD, Hatch RC, Brown J, Crowell WA. Pharmacokinetic and pathological evaluation of gentamicin in cats given a small intravenous dose repeatedly for five days. Can J Vet Res. 1988;52(2):177-80.

Moore RD, Lietman P, Smith CR. Post antibiotic effects in experimental infection models: relationship to in vitro phenomenal and to treatment of infections in man. J Antimicrol Chemother. 1989;31 Suppl D:149-58.

Gunderson BW, Ross GH, Ibrahim KH, Rotschafer JC. What do we really know about antibiotic pharmacodynamics? Pharmacotherapy. 2001;21:302S-18.

Hamilton SF, Evans WE. Accuracy of using pre- and post-dose gentamicin serum concentrations to estimate pharmacokinetic parameters and adjust doses in children and adolescents. Ther Drug Monit. 1981;3(1):57-61.

Frazier DL, Riviere JE. Gentamicin dosing strategies for dogs with subclinical renal dysfunction. Antimicrob Agents Chemother. 1987;31(12):1929-34.

Dickson PL, DiPiro JT, Michael KA, Cheung RP, Hall EM. Effect of hemorrhagic shock on cefazolin and gentamicin pharmacokinetics in dogs. Antimicrob Agents Chemother. 1987;31(3):389-92.