The renal fractional clearance of platinum antitumour compounds in relation to nephrotoxicity.
The fractional renal clearance of platinum relative to inulin was measured in the conscious rat during the period 60-70 min after injection of the nephrotoxic drug, cisplatin, or its non-nephrotoxic analogues (trans-dichlorodiammine platinum II, carboplatin or iproplatin). The fractional clearance of platinum was between 3 and 4 for cisplatin and its analogues. Platinum from cisplatin and its trans isomer is essentially irreversibly bound whilst that from carboplatin and iproplatin is largely reversibly bound to blood proteins. Probenecid and triethanolamine both caused an increase whereas furosemide caused a decrease in the fractional clearance of total platinum from cisplatin. Choline chloride had no nett effect on the fractional clearance of total platinum. Both furosemide and triethanolamine made no significant difference to the severity of cisplatin induced nephrotoxicity. However, probenecid enhanced cisplatin induced nephrotoxicity and choline chloride was capable of blocking cisplatin induced nephrotoxicity. We conclude that the renal tubular transport of platinum is not per se responsible for the nephrotoxicity of platinum compounds. However, in the case of cisplatin, or one of its metabolites, renal tubular transport may be a prerequisite for nephrotoxicity.
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002945:Cisplatin / Q000031:analogs & derivatives / Q000378:metabolism* / Q000633:toxicity; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008657:Metabolic Clearance Rate; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains
D002945:Cisplatin