Prediction of the renal clearance of cimetidine using endogenousN-1-methylnicotinamide

Maiza, Amor; Daley‐Yates, Peter T.

doi:10.1007/bf01073868

Cited by 17 publications

(19 citation statements)

References 33 publications

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“…4), and N M N clearance was 2.5 times the creatinine clearance. This result is similar to that found in rats where N M N clearance was about 3 times the clearance o f inulin [12][13][14], This provides strong evidence that N M N is secreted by the nephron in man and conceiv ably correlates with tubular function. In a smaller unpubli shed study, we have compared N M N clearance with the clearance o f both 5lC rE D T A and creatinine, for subjects with a wide range o f renal function.…”

Section: Discussionsupporting

confidence: 78%

“…The implication o f this is that a marked glomerulo-tubular imbalance exists for these sub jects. Our previous work in rats with site-specific experi mental renal failure of various types has also shown that N M N clearance is able to demonstrate the existence of a glomerulo-tubular imbalance [10,14]. Reidenberg et al [16] and Lin et al [17] using PAH as a marker o f tubular function found that there is not necessarily a proportional decrease in tubular secretion and glomerular filtration with age and certain types o f renal diseases.…”

Section: Discussionmentioning

confidence: 99%

“…Its is extensively secreted by the proximal tubules [9] and is not bound to plasma proteins. We have already shown N M N to be a useful marker of tubular function in animals with various types of acute and chronic experimental renal failure [10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

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Estimation of Renal Tubular Secretion in Man, in Health and Disease, Using Endogenous N-1-Methylnicotinamide

Maiza

Waldek

Ballardie

et al. 1992

Nephron

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We have been investigating the possibility of using the renal clearance of endogenous N-1-methylnicotinamide (NMN) as a marker of renal tubular function. Sixty-three subjects (11 healthy volunteers and 52 patients with renal impairment) were used for this study. The subjects were divided into three groups according to their creatinine clearance: group 1, over 80 ml/min; group 2, between 30 and 80 ml/min, and group 3, less than 30 ml/min. The correlation between NMN and creatinine clearance was compared for each group. A good correlation (r = 0.84) was found for groups 1 and 3 (r = 0.76), whereas for group 2, a poor correlation was found (r = 0.43). For subjects with mild renal impairment (group 2), there was clear evidence of glomerulo-tubular imbalance manifest by a larger variability in NMN clearance than creatinine clearance and an essentially non-parallel decline in these two parameters for this group. When all subjects were grouped together, the relationship between the clearance of NMN and of creatinine was best described by a 3-term polynomial equation (r = 0.93). NMN clearance is a potentially useful non-invasive marker of renal tubular function in man and provides additional information to that provided by the measurement of creatinine clearance alone. This substance should be more fully evaluated as a potential diagnostic aid.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

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Estimation of Renal Tubular Secretion in Man, in Health and Disease, Using Endogenous N-1-Methylnicotinamide

Maiza

Waldek

Ballardie

et al. 1992

Nephron

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“…At variance with nephropathic patients and animals, in which NMN clearance has been shown to decrease with decreasing GFR and to be a good predictor of the clearance of renally secreted drugs [13, 16], in cirrhotic patients, the NMN clearance increases with the severity of liver disease and, therefore, does not correlate with the reported clearances of various renally secreted xenobiotic compounds which have been shown to decrease with increasing liver dysfunction (see Introduction). Caution should also be applied in using NMN as a renal secretion marker in any other disease, until it is demonstrated that its clearance correlates with that of secretion markers, such as p -aminohippurate, which are not reabsorbed.…”

Section: Discussionmentioning

confidence: 94%

“…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].…”

Section: Introductionmentioning

confidence: 99%

Renal Clearance of N<sup>1</sup>-Methylnicotinamide: A Sensitive Marker of the Severity of Liver Dysfunction in Cirrhosis

Orlando

Floreani²,

Napoli³

et al. 2000

Nephron

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Background/Aims: Data have appeared suggesting that an impairment of renal tubular secretion is present in liver cirrhosis, even in the absence of a clinically evident renal dysfunction. To address this question, we evaluated the renal clearance of N¹-methylnicotinamide (NMN), a marker of the renal secretory function, in healthy subjects and patients with liver cirrhosis of increasing severity, but with a normal glomerular filtration rate. Methods: The renal clearances of endogenous NMN, inulin, and creatinine were measured in 14 normal subjects and in two groups of age-matched cirrhotic patients (10 Child A and 10 Child C). In 6 subjects, 2 per group, the concentration dependence of the NMN clearance was also studied, following an oral nicotinamide load. Results: Contrary to expectations, the renal NMN clearance increased in cirrhotic patients, in relation to the severity of liver disease (r = 0.83 with Pugh’s score; p < 0.001). The NMN-to-inulin clearance ratio increased from a control value of 2.2 ± (SD) 0.4 to 3.1 ± 0.2 and 5.2 ± 0.9 in Child A and Child C cirrhotics, respectively (p < 0.001 for all comparisons), indicating that NMN was completely cleared from plasma in the latter patients. Consistently, the analysis of the concentration dependence of the renal NMN clearance revealed the presence of a carrier-mediated reabsorption which apparently was no longer operating in the decompensated patients. Discriminant analysis showed that renal NMN clearance, and NMN-to-creatinine and NMN-to-inulin clearance ratios could all distinguish between the three study groups, with sensitivities and specificities equal or greater than 90%. Conclusions: Contrary to previous proposals, NMN is not a probe of general validity for renal tubular secretion. In particular, due to an imbalance between secretion and reabsorption, its renal clearance in liver cirrhosis cannot be used to determine the degree of tubular secretion of which an individual is capable. However, renal NMN clearance appears to be a very sensitive marker of the severity of liver dysfunction in cirrhosis. The potentialities of this renal parameter as a diagnostic and prognostic test in liver cirrhosis deserve further study.

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Variability in the renal clearance of cephalexin in experimental renal failure

Maiza

Daley‐Yates

1993

Journal of Pharmacokinetics and Biopharmaceutics

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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.

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Prediction of the renal clearance of cimetidine using endogenousN-1-methylnicotinamide

Cited by 17 publications

References 33 publications

Estimation of Renal Tubular Secretion in Man, in Health and Disease, Using Endogenous N-1-Methylnicotinamide

Estimation of Renal Tubular Secretion in Man, in Health and Disease, Using Endogenous N-1-Methylnicotinamide

Renal Clearance of N<sup>1</sup>-Methylnicotinamide: A Sensitive Marker of the Severity of Liver Dysfunction in Cirrhosis

Variability in the renal clearance of cephalexin in experimental renal failure

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