Renal excretion of cephapirin and cephaloridine: Evidence for saturable tubular reabsorption

Arvidsson, Annie; Borgå, Olof; Alván, Gunnar

doi:10.1002/cpt1979256870

Cited by 25 publications

(22 citation statements)

References 4 publications

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“…The pharmacokinetic parameters of carumonam found in our study are in agreement with those reported by others (2,5,7,15;Weidekamm et al,26th ICAAC). With the exception of one study, the reports were concerned with singledose administration.…”

Section: Discussionsupporting

confidence: 93%

“…Carumonam has little or no activity against gram-positive bacteria, and this prevents its use as a single agent for the empiric treatment of seriously ill patients (8). Pharmacokinetic studies after single intravenous administration of 500 to 2,000 mg to healthy volunteers showed that carumonam has a short elimination half-life (1.6 to 1.8 h) and is predominantly excreted via the renal route (2,3,5,7,15 Sample analysis. Plasma and urine samples were analyzed in duplicate for total carumonam by the reverse-phase, ion-pairing, high-pressure liquid chromatography method described previously (2a) and adapted in our laboratory.…”

mentioning

confidence: 99%

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Pharmacokinetics of carumonam after single and multiple 1- and 2-g dosage regimens

Bérubé

Vallée

Panneton

et al. 1988

Antimicrob Agents Chemother

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The pharmacokinetics of carumonam after single and multiple intravenous administration of 1- and 2-g dosage regimens were studied in 12 young male volunteers. Plasma and urine samples were collected in serial order for 24 h and assayed by high-pressure liquid chromatography. The mean elimination half-life of carumonam was not significantly affected by either dosage regimen or single dose versus steady state, ranging from 1.3 to 1.5 h. Mean concentrations at the end of the interval were not influenced by a multiple-dose administration. The normalized volume of distribution was independent of the dose, with values ranging from 0.16 to 0.19 liters/kg. After multiple administration, carumonam was cleared from the body more rapidly: from 96.2 to 121.7 ml/min after 1 g every 8 h, and from 102.1 to 122.3 ml/min after 2 g every 8 h (P less than 0.05). After 24 h, 75.0 to 80.7% of the dose was excreted unchanged in the urine. The protein binding of carumonam to human plasma remained stable at 28%. Carumonam was well tolerated by the volunteers.

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Section: Discussionsupporting

confidence: 93%

mentioning

confidence: 99%

Pharmacokinetics of carumonam after single and multiple 1- and 2-g dosage regimens

Bérubé

Vallée

Panneton

et al. 1988

Antimicrob Agents Chemother

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“…As noted in our earlier study on renal elimination of cephaloridine and cephapirin, the renal clearance of cephapirin decreased when plasma concentrations declined (Arvidsson et al, 1979 Table 3 Difference (in percentage) in renal clearance of acidic amino acids between 07.00 h-10.00 h and 10.00 h-14.00 h during 3 control days in five subjects (C column) and during cephapirin experiment day (E column). Cephapirin was given at 10.00 h. Significance of difference between control and experiment was tested by paired t-test.…”

Section: Discussionmentioning

confidence: 63%

“…(Arvidsson et al, 1979 Uric acid, sodium and osmolality were determined by standard methods in routine use at the hospital.…”

Section: Methodsmentioning

confidence: 99%

Effect of cephapirin on tubular reabsorption of amino acids, uric acid and beta 2‐microglobulin in man.

Arvidsson¹,

Alván²,

Borgå³

et al. 1983

Brit J Clinical Pharma

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Cephapirin, a beta‐lactam antibiotic, was administered intravenously to five healthy subjects in a dose of 1 g. Renal clearances of cephapirin, beta 2‐microglobulin, uric acid and amino acids were measured during the experiment and compared to timed control data, i.e. when no cephapirin was given. Renal clearance of cephapirin decreased when plasma concentrations declined. As protein binding of cephapirin is constant over a wide plasma concentration range, this finding may indicate that cephapirin is reabsorbed in the kidney by a saturable process. Renal clearance of endogenous amino acids, particularly those belonging to the basic group increased after cephapirin. There was no change in renal clearance of beta 2‐microglobulin which excludes a general toxic effect on tubular reabsorption of endogenous substances caused by cephapirin. A flow dependent increase of uric acid clearance was observed. Our results are suggestive of a competition between cephapirin and amino acids for some common step in the tubular reabsorption process.

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“…By using isolated brush border and basolateral membrane vesicles, it has been shown that ,B-lactams are actively transported from the peritubular fluid into the cell, providing a relatively high concentration inside the peritubular cell. The subsequent movement of the compound to the lumen has both active and passive components (2,17,18,31,32). Our study focuses on one of the possible factors that can affect the basolateral step, namely, the concentration of the transported species in the perfusing medium.…”

Section: Discussionmentioning

confidence: 99%

Influence of the unbound concentration of cefonicid on its renal elimination in isolated perfused rat kidneys

Rodríguez

Smith

1991

Antimicrob Agents Chemother

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The effect of variations in plasma protein binding on the renal excretion of cefonicid was assessed by using isolated perfused rat kidneys. Cefonicid exhibits preferential binding ex vivo to human serum albumin (HSA), as opposed to bovine serum albumin (BSA), and is eliminated mainly by tubular secretion, a process that was reported to be dependent on the total drug concentration. This contradicts previous studies with antimicrobial compounds and other drugs of low renal extraction in which the unbound drug concentration was shown to be the driving force for carrier-mediated tubular transport. To clarify this discrepancy, we performed perfusion studies by using 6% BSA at initial concentrations of 200 ,g/ml (n = 6) and 20 Fg/ml (n = 9) and in a combination of 4% BSA plus 2% HSA at initial concentrations of 200 ,ig/ml (n = 4). The excretion ratio [ER = CLR/(f. x GFR)] of cefonicid decreased with increasing unbound concentrations, whereas no apparent relationship with the total concentration was evident. At similar total concentrations of cefonicid, the renal clearance remained unchanged; the secretion clearance increased significantly in the 4% BSA-2% HSA experiments, reflecting the reduced unbound fraction and unbound drug concentration of cefonicid. The excretion ratio data were compatible with a model in which Michaelis-Menten kinetics were required to describe active transport and secretion was dependent on the unbound cefonicid concentration. As a result, changes in plasma protein binding as a result of drug interactions or disease states could significantly influence the tubular transport capability of compounds with low renal extraction.Renal excretion constitutes a major route of elimination of cephalosporins. Glomerular filtration and renal tubular secretion are the main mechanisms by which this group of antimicrobial agents are excreted by the kidneys; of these two, tubular secretion is of particular importance. The pharmacodynamic response and the disposition of drugs with intratubular sites of action can be viewed as being linked by tubular secretion. These variables can be influenced by the presence of plasma protein binding, which in turn can be altered by other drugs and disease states. Hence, it is of utmost televance to consider the relationship between plasma proteid binding and tubular secretion. In fact, despite previous accounts, it is not clear whether renal tubular secretion is a process driven by the total (4,11,33,35) or by the unbound (8, 14-16, 19, 20) drug concentration. The present investigation attempts to systematically examine and clarify the role of protein binding on tubular secretion. In particular, we wanted to explore the influence of the unbound concentration of cefonicid, an expanded-spectrum cephalosporin, on its renal elimination by using the isolated perfused rat kidney model. This model offers the important advantage of being able to measure renal tubular function that is stable over time. It permits direct delivery of substances to the kidneys in definite concentrations...

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Renal excretion of cephapirin and cephaloridine: Evidence for saturable tubular reabsorption

Cited by 25 publications

References 4 publications

Pharmacokinetics of carumonam after single and multiple 1- and 2-g dosage regimens

Pharmacokinetics of carumonam after single and multiple 1- and 2-g dosage regimens

Effect of cephapirin on tubular reabsorption of amino acids, uric acid and beta 2‐microglobulin in man.

Influence of the unbound concentration of cefonicid on its renal elimination in isolated perfused rat kidneys

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