Oseltamivir is an ester prodrug and a potent, selective inhibitor of neuraminidase that results in an inhibition of the release of the influenza virus from host cells and an inhibition of the growth of the influenza virus. Oselta- mivir phosphate is used for the treatment of influenza virus infections [1] . It is used in the treatment and proph- ylaxis of both Influenza virus A and Influenza virus B [2] . Oseltamivir is the most widely used drug but is cur- rently only available as an oral formulation and is eliminated primarily by tubular secretion [3] . The drug is rea- dily absorbed and is converted by hepatic esterase to its active form, oseltamivir carboxylate (OC). The drug is excreted primarily by renal excretion with 60% - 70% of an oral dose appearing in the urine as an active meta- bolite; therefore, dosing must be adjusted in patients with renal impairments [4] [5] . The OC elimination half- life is approximately 6 to 8 h in adults and up to 13 h in children and 36 h in patients with renal failure [6] . The concentrations of a single dose of 14C radiolabeled [2-acetyl-14C]oseltamivir at 10 mg/kg in rats were widely distributed, with the highest tissue concentrations being observed in the small intestine, liver, stomach, and kid- neys 1 h after dosing. The tissue radioactivity concentrations, with the exception of the large intestine, were lower at 6 h and were still detectable 24 h after dosing [7] . The kidney is highly susceptible to toxicants for two reasons: 1) a high volume of blood flows through it and 2) it filters large amounts of toxins, which can concen- trate in the kidney tubules resulting in systemic toxicity causing a decreased ability to excrete bodily wastes [8] . This study was conducted to evaluate the possible nephrotoxic effects caused by therapeutic and prophylactic dose regimens of Oseltamivir available pharmaceutically as fluffy^® produced by Julphar, Gulf Pharmaceutical Industries, Ras Al-Khaimah, UAE and imported by the medical authorities in Iraq. This study focused on some selected parameters of kidney function supported by a histopathological study.

Biochemical markers play an important role in accurate diagnoses, assessing risks and adopting therapies that improve clinical outcomes. As markers of renal function, serum creatinine, blood urea nitrogen (BUN) and uric acid are routinely used for analysis [15] . Elevated uric acid is one of the most important risk factors for cardio- vascular disease; it plays a significant role in the development of renal disease and metabolic syndrome, and high serum urate levels are usually associated with defects in uric acid transport [16] . An elevated uric acid level often precedes kidney disease [17] . The repeated dosing of oseltamivir at 1 mg/kg BW throughout the period of the present study resulted in distinct pathological changes in the kidneys of the rats in both treated groups and was shown in Figures 1-5.

Urea is a major nitrogenous end product of the protein and amino acid catabolism produced by the liver and is distributed throughout the intracellular and extracellular fluid [15] . Low blood urea levels are seen in trauma and surgery and are associated with the use of some drugs, anabolic steroid use and malnutrition [18] . The signifi- cant reduction in the blood urea nitrogen concentration throughout the experimental period may be attributed to impairment of the urea cycle (in the liver) leading to the reduced production of metabolic products [19] . This is an indication of an abnormality in the physiological excretion of urea caused by a non-renal factor [20] . We considered that the reduction in the blood urea nitrogen level was due to the hepatotoxic effects of oseltamivir

dosed at 1 mg/kg BW for six weeks. We reached this conclusion by histopathological analysis and other liver function tests including alaninaminotrasferase (ALT), aspartate aminotrasferase (AST), alkaline phosphatase (AP), total bilirubin, conjugated and non-conjugated bilirubin and total serum protein [21] . The liver is the site of the urea cycle. However, the effects of the drug were not obvious at one week of dosing because the BUN level in the T1 group was similar to that in the control group.

Creatinine is commonly used as a measure of kidney function, and the calculation of the glomerular filtration rate may be derived from the serum creatinine level [22] . A diagnosis of renal failure is usually suspected when the serum creatinine is greater than the upper limit of the normal interval; in chronic renal failure and uremia, an eventual reduction in the excretion of creatinine by both glomeruli and tubules occurs [23] . These events are confirmed by histopathological findings in the kidneys of the rats treated with 1 mg/kg BW of oseltamivir for six weeks, which included cystic dilation of the cortical renal tubules with complete dissolution of their epitheli- al lining (Figure 3) and thickening of the Bowman’s capsule (Figure 4).

Oseltamivir induced kidney injury in rats treated with 0.1 mg/kg BW for one and six weeks through the in- creased level of uric acid (table 1). In other studies in rats, experimental hyperuremia (induced by oxonic acid) has also been associated with the development of mild renal disease, characterized by mild proteinuria, renal ar- teriolar changes, glomerular hypertrophy, tubulointerstitial fibrosis, and eventually glomerulosclerosis [24] . In- terestingly, when hyperuremia was induced in rats with preexisting renal disease (i.e., in which one entire kid- ney and two thirds of the other kidney had been removed), their renal lesions were dramatically worse than in similar rats without hyperuremia [25] . This suggests that the hyperuremia may not only cause renal disease but also exacerbate preexisting renal disease. The mechanism by which uric acid might cause renal disease was re- vealed by micropuncture studies that demonstrated that elevated uric acid (3.1 ± 0.2 mg/dL) caused glomerular hypertension and cortical vasoconstriction [26] . These changes would be expected to induce glomerular damage and tubular ischemia. In addition, uric acid stimulated inflammatory mediators in vascularcells, including C- reactive protein and monocyte chemoattractant protein-1p [27] [28] and vasoconstrictive factors such as throm- boxane [25] . After oral administration, oseltamivir is rapidly hydrolyzed to its active metabolite oseltamivir carboxylate (OC), which is then excreted by glomerular filtration and renal tubular secretion without further metabolism [29] . When rats are unable to hydrolyze the oseltamivir phosphate sufficiently to its metabolite, an excessive amount of phosphate will accumulate. This would negatively affect the dietary calcium/phosphate ra- tio in species known to be sensitive to this type of change and would consequently lead to mineralization of the kidney [30] .

The results of this study suggest that the rats that had been exposed repeatedly to 1 mg/kg BW of oseltamivir experienced several deleterious effects on kidney function depending on the period of dosing, as shown by se- rum biochemical markers. Oseltamivir, when given at low therapeutic doses for prophylaxis (six weeks) caused renal damage; therefore, kidney and liver function tests must be performed during OM prophylaxis therapy.