Pharmacokinetics of etoposide in rats with uranyl nitrate (UN)-induced acute renal failure (ARF): optimization of the duration of UN dosing.

A uranyl nitrate-induced model of acute renal failure (UN-ARF) for various time periods was used to study its effect on the disposition of several drugs like chlorzoxazone, clarithromycin, vancomycin, methotrexate etc. An attempt to optimize the duration of UN dosing with respect to the pharmacokinetics of etoposide in rats was carried out after intravenous (i.v.) dosing of UN at 5 mg/kg for 1, 3, 5 and 7 days. Irrespective of the duration of UN dosing apart from day 1, ARF was observed, with significantly increased serum levels of creatinine (0.36 +/- 0.11 for controls vs 2.44 +/- 0.72 [day 7] for UN-ARF rats) and urea (33.71 +/- 9.46 for controls vs. 169.2 +/- 9.71 [day 5] for UN-ARF rats) in all the UN-treated groups. It has been reported that ARF may alter the pharmacokinetics (PK) and the exposure of renally eliminated drugs. Further, as exposure to etoposide has a correlation with toxicity, the need to investigate the possible alterations in etoposide pharmacokinetics in the UN-ARF model could be of significance. The PK of etoposide was therefore investigated in control and UN-ARF rats after a single i.v. dose of 25 mg/kg. The concentrations of etoposide in the plasma were determined by high- performance liquid chromatography (HPLC) method with fluorescence detector set at excitation and emission wavelengths of 380 and 520 nm respectively. The metabolic stability of etoposide was investigated in rat liver microsomes prepared from control and UN-ARF treated rats. The PK results showed increased plasma levels and systemic exposure to etoposide (19.97 +/- 2.12 for control vs 29.03 +/- 2.32, 34.45 +/- 3.37, 34.19 +/- 2.98 for 3, 5 and 7day UN-treated groups respectively), i.e. for all UN-ARF groups except for 1-day UN-ARF rats (20.06 +/- 1.53). Incubation with liver microsomes from UN-ARF rats treated for up to 5 days and control rats showed no significant difference in etoposide metabolism suggesting that the CYP3A4 isoenzyme responsible for the metabolism of etoposide was not considerably expressed thereby leading to the conclusion that 3 days UN dosing was sufficient to induce ARF in rats, and that the dose of etoposide required needs to be monitored due to altered PK.