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

Abstract

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.

Altered disposition of drugs in acute renal failure rat models: drug development strategies and perspectives

“…2007 [19] Etoposide (33419-42-0) Uranyl nitrate induced ARF Etoposide plasma levels increased by almost 35 to 45 % in ARF rats.…”

“…Intravenous administration of uranylnitrateatadoseof 5mg/kg onced ailyfor3to7days cani nduceARF in rats [19].The ARF ischaracterized byincreased serum/ plasmalevelsof bothcreatinine and urea, asw ell asa precipitous drop of the glomerularfiltration rate. Itis believed toh aved irectimpacton the hemodynamics leading tostep-wisechangesin the renalf unction and ultimatelycausing tubularnecrosis.Although notu niversal,some researchshowed thatARF condition after uranylnitratemayalsobeassociated withanaltered hepaticfunction/metabolism [34].…”

“…Renale xcretion:A sdocumented in all studiesane xpected outcome in ARF iss everereduction of renal clearanceapplicable tobothparentdrugand associated metabolites.Ifthe sole contributorand/ormajorpathwayfort he overall elimination isr enalclearance,then accumulation of the substrateisbound tohappen asexemplified bys ubstratess uchasetoposide (CAS 33419-42-0) [19], telithromycin (CAS 191114-48-4) [20], topotecan( CAS 123948-87-8) [26], adriamycin [45], etc.Inthe eventthatcertain CYP expressionsarealsoinduced during ARF, itispossible thatmetabolicc learanceo fthe drugafteroraldosing maygetmoreaffected thanintravenous dosing in ARF rats.Henced epending on the non-renalclearancep athways duetoe nhanced metabolism,the totalbodyclearancem aygets omewhat tempered asillustrated bys ubstratess uchasmycophenolica cid (CAS 24280-93-1) [22], DA-7867 [25], DA-125 [44]etc. Biliary excretion:A sillustrated byt wocasestudies bothp arentdrugand metabolite(s)canbep redominantlyexcreted viab iliary pathwayduring ARF.Since suchbiliary excretory pathways wereo fl imited applicability in control rats undernormalconditions,itappears thatARF conditionsmaypromptalternativee xcretory pathways forr educing the drugburden on the body.Asexemplified in the caseo fcyclosporine there maybed iminished bile secretion and pert he datagenerated from indocyanine green therem aybeasignificantdelayin the biliary excretion of the compound during ARF [68].Onthe contrary,the biliary excretion of 7-O-glucuronica cid conjugateo fm ycophenolica cid was significantlyincreased in ARF rats [22].Asaresultof rapid enterohepaticc ycling of the Phase2metabolite and poorr e-absorption from the lumen,therewasa suggestion of ani ncreased risko fg astrointestinald isorders [22].…”

“…Inthis context,Venkatesh etal. optimized the uranylnitrateinduced ARF ratmodel toevaluatethe disposition kinetics of etoposide [19].Ass howni nFig. 3,one of the keydesign considerationsw ast he numberof uranyln itrate dosing days fort he maninfestation of full blownARF as measured bys erumcreatinine valueand pharmacokineticsurrogatee xposureand totalbodyclearance( 1,3, 5o r7days).…”

“…3:O ptimization of the ARF ratmodel fordefinitivepharmacokineticinvestigation (datafrom reference [19]wasused in the construction of the plot). First histogramrepresents etoposide exposure;s econd histogramrepresents totalbody clearance.…”