Altered intravenous pharmacokinetics of topotecan in rats with acute renal failure (ARF) induced by uranyl nitrate: do adenosine A1 antagonists (selective/non-selective) normalize the altered topotecan kinetics in ARF?
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.
Mustafa
S
S
Drug Metabolism and Pharmacokinetics, Discovery Research, Dr Reddy's Laboratories Ltd, Miyapur, Hyderabad, India.
Venkatesh
P
P
Pasha
K
K
Mullangi
R
R
Srinivas
N R
NR
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D058916:Adenosine A1 Receptor Antagonists; D000818:Animals; D002110:Caffeine / Q000008:administration & dosage; D004347:Drug Interactions; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019772:Topotecan / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014502:Uranyl Nitrate / Q000633:toxicity; D014970:Xanthines / Q000008:administration & dosage; D015262:Xenobiotics / Q000008:administration & dosage / Q000493:pharmacokinetics
D058916:Adenosine A1 Receptor Antagonists; D014970:Xanthines; D015262:Xenobiotics; D014502:Uranyl Nitrate; D002110:Caffeine; D019772:Topotecan; C049140:1,3-dipropyl-8-phenylxanthine