Variability in the renal clearance of cephalexin in experimental renal failure

Abstract

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.

Renal Excretion of Vancomycin in Rats with Acute Renal Failure

“…It is, therefore, necessary to understand not only changes in glomerular filtration but also those in the tubular secretion of a drug in renal failure. The use of phenolsulphonephthalein and N-1 -methylnicotinamide have been proposed for the evaluation of these two functions simultaneously (Hori et a1 1985b;Maiza & Daley-Yates 1993). Both phenolsulphonephthalein and N-I-methylnicotinamide are eliminated by glomerular filtration and tubular secretion in the kidney.…”

A general empirical model for renal drug handling in pharmacokinetic analyses

“…There is concern that the INH oversimplifies renal dysfunction and that obvious examples of an imbalance between glomerular and tubular function are not accommodated . Bricker et al also acknowledges this limitation: ‘…a number of disease entities exist where a disproportionate involvement of one or more specific tubular functions may dominate the clinical picture’ (p.77) .…”

“…Many drugs, including metformin, beta‐lactam antibiotics, angiotensin‐converting enzyme inhibitors, diuretics, and nonsteroidal anti‐inflammatory agents, are extensively handled by tubular anionic and cationic transporters. There is a growing body of evidence to suggest that, for these drugs, changes in GFR may not adequately reflect changes in tubular clearance mechanisms . This being the case, a nonlinear relationship between GFR and renal drug clearance could be theorized.…”

Renal Clearance of N¹-Methylnicotinamide: A Sensitive Marker of the Severity of Liver Dysfunction in Cirrhosis

“…It has been proposed as a marker of the renal tubular function, since it is a prototypical substrate for the organic cation transporter and is not bound to plasma proteins [11, 12]. As a matter of fact, NMN has been shown to be a useful probe for assessing the renal tubular secretion in animals with various types of experimental renal failure [13, 14]as well as in patients with nephropathies of varying etiologies [15, 16]. NMN appears preferable to anionic secretion markers, such as p -aminohippurate and diodrast, when, due to the presence of other anionic substances, the tubular secretion of the latter markers can be inhibited [15].…”