The renal effects of N10-propargyl-5,8-dideazafolic acid (CB3717) and a non-nephrotoxic analogue ICI D1694, in mice.
N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)- N-methylamino]-2-thenoyl)-L-glutamic acid (ICI D1694) is an analogue of the thymidylate synthase inhibitor, N10-propargyl-5,8-dideazafolic acid (CB3717). CB3717 was found to be active in early clinical studies, but its use was limited by nephrotoxicity. ICI D1694 is a more potent antitumour agent than CB3717 and is also more water soluble. Previous studies have shown ICI D1694 to be non-toxic to the kidney following a single administration but its renal effects after chronic administration are unknown. To assess these effects, and further define the time course and dose relationship of CB3717-induced renal damage, an assay of glomerular filtration rate (GFR) has been developed which can be used in mice and hence in the screening of novel compounds. The 14C-inulin clearance assay developed was used to show a linear relationship between CB3717 dosage and renal damage (r = - 0.989) following a single bolus dose (50-200 mg kg-1), in mice. CB3717-induced renal damage is persistent (greater than 6 weeks) and renal scarring was noted. ICI D1694 has been shown to be non-nephrotoxic following weekly administration of 250 mg kg-1 for 6 weeks. Measurement of GFR has been shown to be a more sensitive indicator of impaired renal function than plasma urea and creatine concentration, and the measurement of plasma creatinine concentration in particular, appears to be without value in the screening of potential nephrotoxins in certain mouse strains.
Clinical Pharmacology Team, Drug Development Section, Sutton, Surrey, UK.
D I
DI
Jodrell
D R
DR
Newell
S E
SE
Morgan
S
S
Clinton
J P
JP
Bensted
L R
LR
Hughes
A H
AH
Calvert
D000818:Animals; D002250:Carbon Radioisotopes; D002945:Cisplatin / Q000009:adverse effects; D003404:Creatinine / Q000097:blood; D005260:Female; D005492:Folic Acid / Q000009:adverse effects / Q000031:analogs & derivatives*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007444:Inulin / Q000097:blood / Q000493:pharmacokinetics; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D007674:Kidney Diseases / Q000097:blood / Q000139:chemically induced; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D011799:Quinazolines / Q000009:adverse effects*; D013876:Thiophenes / Q000009:adverse effects*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D014508:Urea / Q000097:blood
D002250:Carbon Radioisotopes; D011799:Quinazolines; D013876:Thiophenes; C031662:CB 3717; D014508:Urea; D007444:Inulin; D005492:Folic Acid; D003404:Creatinine; D013940:Thymidylate Synthase; C068874:raltitrexed; D002945:Cisplatin