Altered intravenous pharmacokinetics of topotecan in rats with acute renal failure (ARF) induced by uranyl nitrate: Do adenosine A₁antagonists (selective/non-selective) normalize the altered topotecan kinetics in ARF?

Abstract

A series of exploratory investigations with multiple agents was carried out in normal rats and in rats with uranyl nitrate-induced acute renal failure to understand the disposition characteristics of intravenous topotecan (TPT) used as a model substrate. The disposition of TPT was unaltered in normal rats when treated with methotrexate, whereas treatment with probenecid increased the systemic exposure of TPT. In case of uranyl nitrate-induced acute renal failure (UN-ARF) rats, the systemic exposure of TPT was increased when compared with normal rats, whereas in UN-ARF rats treated with probenecid a further reduction in renal clearance of TPT was noted as compared with that of UN-ARF induced rats. Thus, TPT may be involved in the tubular secretory pathway when a passive glomerular filtration pathway for elimination was not possible. The disposition of TPT did not normalize in UN-ARF rats when treated with caffeine, a non-selective adenosine A1 receptor antagonist, whereas the selective adenosine A1 receptor antagonist (1,3-dipropyl-8-phenylxanthine, DPPX) normalized TPT pharmacokinetic disposition by improving renal function. Renal excretion studies demonstrated that CLR improved by almost fivefold following DPPX treatment in ARF rats. In addition, the qualitative stability/metabolism pattern of TPT in liver microsomes prepared from various groups of rats (normal rats, UN-ARF rats, rats treated with DPPX, and UN-ARF rats treated with DPPX) was found to be similar. In summary, using a pharmacokinetic tool as a surrogate, it has been shown that the pharmacokinetic disposition of TPT improved considerably upon treatment with DPPX, a selective adenosine A1 antagonist.

Involvement of Rat and Human Organic Anion Transporter 3 in the Renal Tubular Secretion of Topotecan [(S)-9-Dimethylaminomethyl-10-hydroxy-camptothecin hydrochloride]

“…A population pharmacokinetic analysis indicated that tubular secretion in addition to glomerular filtration is involved in topotecan renal clearance in humans (Mould et al, 2002). Prior studies in murine species demonstrated that the renal clearance of topotecan was significantly reduced by probenecid, a typical inhibitor of organic anion transporters, suggesting that topotecan undergoes renal tubular secretion via organic anion transporter(s) (Zamboni et al, 1998;Mustafa et al, 2006). However, the molecular mechanism of renal tubular secretion of topotecan has not been elucidated.…”

“…Many investigators have reported on the systemic and renal disposition of topotecan in various animals and humans (Herben et al, 1996(Herben et al, , 2002Zamboni et al, 1998;Hartmann and Lipp, 2006;Mustafa et al, 2006). Topotecan is primarily excreted into urine as both lactone and hydroxyl acid forms, accounting for approximately 49% of the dose administered i.v.…”

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

“…Mustafa et al [26] Topotecan (123948-87-8) Uranyl nitrate induced ARF After i. v. dosing, the AUC values of topotecan was drastically reduced in ARF rats relative to control rats. The addition of probenecid further increased the exposure of topotecan in ARF rats.…”

“…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].…”

“…attempted tonormalizeARF induced byuranylnitrateusing aselectiveadenosine A1receptorantagonist 1,3-dipropyl-8-phenylxanthine (CAS 85872-53-3)( DPPX) [26].Interestingly,topotecanwasu sed asaprobetoi nvestigatethe role of DPPX in reversing ARF bymonitoring the pharmacokineticsof topotecani nARF rats and ARF rats thatw erep retreated differentdosesof DPPX [26].Asac onsequenceo fthe improvementof renal function byDPPX pretreatment,the pharmacokinetics of topotecanconsiderablyimproved in the ARF rats [26].Although the pharmacokineticsof topotecanwas notr estored tothe levelsobserved in control rats,there wasasuggestion thatadenosine A1receptorantagonist mayamelioratethe insultt othe kidney.Therefore,this proposed pharmacokineticstrategymayprovide ano pportunity forfuturep reclinicali nvestigationst om ake a productdecision on investigationald rug(s)i nd evelopment,if therei sasignificantconcernrelated toARF interactions.Previously,Clark etal. used avessel dilatorto improvethe conditionsof renali nsultincluding tubular necrosis [61].The datafrom thisexploratory worksuggested thatt he useo favessel dilatordecreased the serumcreatinine and blood ureanitrogen levelsconsiderablyascompared ton on treated ARF rats [61].Also, mortality wasdrasticallyreduced and therewasasignificantimprovementof the tubularnecrosisfindings.Unfortunately,thisinvestigation did notinclude anactive pharmacokineticstrategyt oconfirmthe reversibility of the system using pharmacokineticsast he surrogate (i. e. control rats versus ARF rats versus revived ARF rats) [61].…”