Abstract
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.
Highlights
In order to define the volume of distribution of '4C-inulin, in female Balb C and in male C57/DBA2 Fl hybrid mice, '4C-inulin pharmacokinetics were studied in normal mice
When '4C-inulin concentrations calculated by regression analysis were compared with the observed concentrations, to estimate the precision of the fit, linear regression (r) values of 0.986 and 0.951 were obtained, indicating that the data were well described by a single exponential term
In female Ralb C mice the volume of distribution, 219 ml kg-', was lower than in male C57/DBA2 hybrid mice and the glomerular filtration rate (GFR) was lower at 15.3mlmin' kg-'
Summary
The measurement of glomerular filtration rate (GFR) in mice. In order to define the volume of distribution of '4C-inulin, in female Balb C and in male C57/DBA2 Fl hybrid mice, '4C-inulin pharmacokinetics were studied in normal mice. (0.01 ml g-' = 0.05 jiCi g' body weight), via a tail vein at time to. Five mice were killed at time points predicted to fall in the elimination phase of inulin clearance i.e. 30, 40, 50 and 60 min. 0.1 ml of separated plasma was added to 1.0 ml of mixed quaternary ammonium hydroxides in toluene (NCS solubiliser, Amersham Corp., Illinois, USA) in a glass scintillation vial and incubated (40°C) overnight. Inulin clearance and GFR was calculated using; Clearance = Va. In drug treated mice, 0.05 IACi g-' body weight of 14C-
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