This study forms a part of an investigation into the extent to which the type of renal damage influences the renal clearance of drugs. We have already demonstrated an effect of different types of experimental
renal failure (ERF) on the renal clearance of two
cations:
cimetidine, a
drug that is filtered and secreted by the nephron, and
lithium, which is filtered and reabsorbed by more than one segment of the nephron. In this report the renal clearance of
cephalexin (CLCEX) is investigated, a
drug that has a different mode of renal elimination, since it is filtered, secreted, and reabsorbed by the proximal tubules. The aim was to extend our earlier studies to an organic
anion, and to provide an opportunity to evaluate the feasibility of using the renal clearance of N-1-methylnicotinamide (NMN) to predict the renal clearance of anionic drugs in
renal failure. Different models of site-specific ERF have been developed in the rat; proximal tubular
necrosis (induced by
cisplatin), papillary
necrosis (induced by 2-bromoethylamine), and
glomerulonephritis (induced by
sodium aurothiomalate or by antiglomerular basement membrane
antibodies). Glomerular function (GFR) was assessed by the clearance of
inulin (CLNULIN), and tubular function was assessed by the clearance of endogenous NMN (CLNMN). OUr results show that even if the models of ERF used were not absolutely site-specific, glomerular function and tubular function did not decrease to the same extent in the different ERF. Therefore, glomerulo-tubular imbalance existed, which is incompatible with the "intact nephron hypothesis," i.e., the site of the damage along the nephron and not only the degree of renal dysfunction, is a potential source of variability in the clearance of certain drugs. The renal clearance of
cephalexin was estimated more accurately by CLNMN than GFR (r = 0.90). We conclude that the clearance of the endogenous
cation NMN can be used to predict the renal clearance of drugs that are not only filtered by the glomeruli but also secreted and/or reabsorbed by the proximal tubules, and in the limited examples investigated appears to apply to both anionic and cationic compounds. In this respect the GFR alone was not an adequate parameter for the prediction of the renal clearance of such drugs.