The Nephrotoxic Impact of Oseltamivir in Male Albino Rats after Repeated Exposure

Falah Muosa Kadhim Al-Rekabi

College of Vet Medicine, University of Baghdad, Baghdad, Iraq.

DOI: 10.4236/pp.2014.55058                

Abstract

The effects of oseltamivir administration, effectively against influenza viruses A and B, on some selected parameters of rat kidney function were investigated to evaluate its possible nephrotoxic effects. Eighteen (18) albino male Wistar rats with body weights ranging from 150 - 190 g were divided into three groups, the first group (T1) was treated orally with 1 mg/kg BW as a therapeutic dose of oseltamivir for 7 consecutive days. The second group (T2) was treated with the same dose for six weeks, while the control group was dosed with distilled water. The results revealed a significant increase (P < 0.05) in blood urea nitrogen (BUN), serum uric acid and serum creatinine in group T2, while the T1 group showed a significant increase (P < 0.05) in serum uric acid only. Kidney histopathological lesions in the T1 rats showed atrophy of the glomerular tufts, dilation of the Bowman’s space, deposition of hyaline droplets within the lumen of the proximal and distal convoluted renal tubules, a cloudy swelling of the epithelial cells lining the renal tubules with perivascular lymphocytic cuffing and severe congestion of the interstitial renal blood vessels. The kidneys of the T2 rats showed necrosis of the epithelial cells lining the renal tubules and cystic dilation with complete dissolution of their epithelial linings. There was vacuolation of the glomerular tuft with proliferation of the parietal layer of the Bowman’s capsule, and a serum protein presence in the glomerular space. Mild interstitial fibrosis and thickening of the Bowman’s capsule were also observed. Similarly, there was fibrous thickening of the kidney capsule with mild medullary interstitial fibrosis. In conclusion, oseltamivir administered in repeated doses to rats induced some deleterious nephrotoxic effects in a time-dependent manner.

Keywords

Olseltamivir, Nephrotoxic, Albino Rats, Repeated Exposure

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Shigeru, O., Eiichi, N.M.K., Yukiya, S. and Daisuke, K. (2009) Penetration of Oseltamivir and Its Active Metabolite into the Brain after Lipopolysaccharide-Induced Inflammation in Mice. Journal of Pharmacy and Pharmacology, 61, 1397-1400. http://dx.doi.org/10.1211/jpp.61.10.0018
[2]	Bardsley, E.A. and Noble, S. (1999) Oseltamivir. Drugs, 58, 851-860. http://dx.doi.org/10.2165/00003495-199958050-00007
[3]	Chairat, K., Tarning, J., White, N.J. and Lindegardh, N. (2013) Pharmacokinetic Properties of Anti-Influenza Neuraminidase Inhibitors. Journal of Pharmacy and Pharmacology, 53, 119-139.
[4]	Saw, J.T. and Hong, L.W. (2007) Oseltamivir in the Treatment of Avian Flu (H5N1). JASA, 2, 46-49.
[5]	He, G. (1999) Clinical Pharmacokinetics of the Prodrug Oseltamivir and Its Active Metabolite Ro 64-0802. Clinical Pharmacokinetics, 37, 471-484. http://dx.doi.org/10.2165/00003088-199937060-00003
[6]	Robson, R.A., Buttimore, K., Lynn, M.B. and Ward. P. (2006) The Pharmacokinetics and Tolerability of Oseltamivir Suspension in Patients on Hemodialysis and Continuous Ambulatory Peritoneal Dialysis. Nephrology, Dialysis, Transplantation, 21, 2556-2562. http://dx.doi.org/10.1093/ndt/gfl267
[7]	Sweeny, D.J., Lynch, G, Bidgood, A.M., Lew, W., Wang, K.Y. and Cundy, K.C. (2000) Metabolism of the Rat Influenza Neuraminidase Inhibitor Prodrug Oseltamivir in the Rat. Drug Metabolism and Disposition, 7, 737-774.
[8]	Emily, M. (2007) Toxicity. In: Cutler, J., Ed., Encyclopedia of Earth, Cleveland, Washington DC.
[9]	Hafez, E.S.E. (1970) Reproduction and Breeding Techniques for Laboratory Animals. Lea and Febiger, Philadelphia.
[10]	Luna, L.G. (1968) Manual of Histology Staining Methods of the Armed Forces Institute of Pathology. 3rd Edition, McGraw Hill Book Co., New York.
[11]	Fossati, P., Prencipe, L. and Berti, G. (1980) Use of 3,5-Dichloro-2-Hydroxybenzenesulfonic Acid/14-Aminophenazone Chromogenic System in Direct Enzymic Assay of Uric Acid in Serum and Urine. Clinical Chemistry, 26, 227-231.
[12]	Fawcett, J.K. and Scott, J.E. (1960) A Rapid and Precise Method for the Determination of Urea. Journal of Clinical Pathology, 13, 156-159. http://dx.doi.org/10.1136/jcp.13.2.156
[13]	Bartels, H. and Bohmer, M. (1971) Eine Mikromethode zur Kreatininbestimmung. Clinical Chimica Acta, 32, 81-85.
[14]	Joda, M. (2008) The Progressive Statistical Analyses by Using SPSS. 1st Edition, Churchill Livingstone, Edinburgh.
[15]	Gowda, S., Desai, P.B., Kulkarni, S.S., Hull, V.V., Math, A.A.K. and Vernekar, S.N. (2010) Marker of Renal Function Tests. North American Journal of Medical Sciences, 4, 170-173.
[16]	Heinig, M. and Johnson, R.J. (2005) Role of Uric Acid in Hypertension, Renal Diseases and Metabolic Syndrome. Cleveland Clinic Journal of Medicine, 12, 1059-1064. http://dx.doi.org/10.3949/ccjm.73.12.1059
[17]	Iseki, K., Oshiro, S., Tozawa, M., Iseki, C., Ikemiya, X. and Takishita, S. (2001) Significance of Hyperuricemia on the Early Detection of Renal Failure in a Cohort of Screened Subjects. Hypertension Research, 24, 691-697. http://dx.doi.org/10.1291/hypres.24.691
[18]	Pagana, K.D. (2002) Mosby’s Manual of Diagnosis and Laboratory Tests. Mosby, St. Louis.
[19]	Rodwell, V.W. (1996) Catabolism of Proteins and Amino Acid Nitrogen. In: Murray, R.K., Granner, D.K., Mayes, P.A. and Rodwell, V.W., Eds., Harpers Biochemistry, 24th Edition, Prentice-Hall International, Upper Saddle River, 305-308.
[20]	Segasolhy, M., Swoninalhua, M. and Kong, N.C. (1994) Acute Renal Failure in Folciparum Malaria. Medical Journal of Malaysia, 49, 412-415.
[21]	Al-Rikabi, F.M.K. (2012) Evaluation of Selected Parameters of Rat Liver Injury Following Repeated Administration of Oseltamivir for Different Periods. Iraqi Journal of Veterinary Medicine, 1, 137-144.
[22]	Miller, W., Myers, G., Ashwood, E., Killeen, A.A., Wang, E., Thienpont, L.M., et al. (2005) Creatinine Measurement State of the Art in Accuracy and Interlaboratory Harmonization. Archives of Pathology & Laboratory Medicine, 3, 297-304.
[23]	Edmund, L. and David, J. (2006) Kidney function tests. In: Burtis, C., Ashwood, E. and Burns, D., Eds., Tietz Textbook of Clinical Chemistry and Molecular Diagnostics, 24th Edition, Elsevier, New Delhi, 797-808.
[24]	Nakagawa, T., Mazzali, M., Kang, D.H., Kanellis, J., Watanabe, S., Sanchez-Lozada, L.G., et al. (2003) Hyperuricemia Causes Glomerular Hypertrophy in the Rat. American Journal of Nephrology, 23, 2-7. http://dx.doi.org/10.1159/000066303
[25]	Kang, D.H., Nakagawa, T., Feng, L., Watanabe, S, Han L, Mazzali M., et al. (2002) A Role for Uric Acid in the Progression of Renal Disease. Journal of the American Society of Nephrology, 13, 2888-2897. http://dx.doi.org/10.1097/01.ASN.0000034910.58454.FD
[26]	Sanchez-Lozada, L.G., Tapia, E., Avila-Casado, C., Soto, V., Franco, M., Santamaría, J., et al. (2002) Mild Hyperuricemia Induces Glomerular Hypertension in Normal Rats. American Journal of Physiology. Renal Physiology, 283, F1105-F1110.
[27]	Kang, D.H., Park, S.K., Lee, I.K. and Johnson, R.J. (2005) Uric Acid-Induced C-Reactive Protein Expression: Implication on Cell Proliferation and Nitric Oxide Production of Human Vascular Cells. Journal of the American Society of Nephrology, 16, 3553-3562. http://dx.doi.org/10.1681/ASN.2005050572
[28]	Kanellis, J., Watanabe, S., Li, J.H., Kang, D.H., Li, P., Nakagawa, T., et al. (2003) Uric Acid Stimulates Monocyte Chemoattractant Protein-1 Production in Vascular Smooth Muscle Cells Via Mitogen-Activated Protein Kinase and Cyclooxygenase-2. Hypertension, 41, 1287-1293. http://dx.doi.org/10.1161/01.HYP.0000072820.07472.3B
[29]	Abe, M., Smith, J., Urae, A., Barrett, J., Kinoshita, H. and Rayner, C.R. (2006) Pharmacokinetics of Oseltamivir in Young and Very Elderly Subjects. Annals of Pharmacotherapy, 40, 1724-1730. http://dx.doi.org/10.1345/aph.1H174
[30]	Farrely, J. (2001) Pharmacologists’ Review. Application Number 21-246, Center for Drug Evaluation and Research, 1-18.