Alteration of pharmacokinetics and nephrotoxicity of cisplatin by alginates.
This study was undertaken to demonstrate that alginates could form a complex with cisplatin and that the pharmacokinetics and nephrotoxicity of cisplatin could be altered by this complexation. The complexes were prepared with alginates of mean molecular weights of 10000 (AL-1) and 40000 (AL-2). The plasma clearances of cisplatin-alginate complexes were significantly reduced when compared with the drug alone. Urinary excretion of platinum (Pt) was increased when animals were dosed with the cisplatin-AL-1 complex, but not with the cisplatin-AL-2 complex. Renal clearance of cisplatin, when administered alone, was more rapid during the first 2 h than the rest of the study period (96 h) and was higher than its plasma clearance, which is consistent with irreversible binding of cisplatin to plasma protein. On the other hand, renal clearance of cisplatin-alginate complexes was not highly time dependent, and the values were more similar to those of plasma clearance. Complexation of cisplatin with alginates, especially AL-1, inhibited the accumulation of Pt in the kidneys and reduced blood urea nitrogen elevation by cisplatin. The in vitro antitumor activities against U937, P388, and cisplatin-resistant P388 (P388/cisplatin) cells were similar among cisplatin and its alginate complexes. These studies indicated that the pharmacokinetics and nephrotoxicity of cisplatin could be altered through complexation with alginate by (1) reducing cisplatin clearance, (2) inhibition of Pt accumulation of in the kidneys, and (3) reduction of apparent nephrotoxicity without decrease in in vitro antitumor activity.
Imai
T
T
Faculty of Pharmaceutical Sciences, Kumamoto University, Japan.
Fujii
K
K
Shiraishi
S
S
Otagiri
M
M
D000464:Alginates / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D002945:Cisplatin / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D004347:Drug Interactions; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured
D000464:Alginates; D000970:Antineoplastic Agents; D002945:Cisplatin