Influence of Binding on the Pharmacologic Activity of Antibiotics

Kunin, Calvin M.; Craig, William A.; Kornguth, Margaret L.; Monson, Roberta A.

doi:10.1111/j.1749-6632.1973.tb20483.x

Cited by 140 publications

(73 citation statements)

References 14 publications

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“…It seems evident that there is a reabsorptive mechanism for gentamicin in the proximal tubule, the major portions of which are situated in the cortex. High affinity of gentamicin for kidney cell particulates has been reported (20), and the filtered compound was probably bound to the intracellular substances after crossing the luminal membrane, and concentration buildup ensued. Accumulation of gentamicin in the renal tissue occurs in animals (H. Whalig, Proc.…”

Section: Resultsmentioning

confidence: 99%

Renal Extraction of Gentamicin in Anesthetized Dogs

Chiu¹,

Brown²,

Miller³

et al. 1976

Antimicrob Agents Chemother

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The tubular handling of gentamicin (G) and its intrarenal distribution were determined to elucidate the mechanism of G accumulation in the kidney. At a serum level of 11.1 ± 0.5 μg/ml (10 animals), as maintained by constant infusion for 5 h, serum Na + and K + , arterial pressure, effective renal plasma flow and glomerular filtration rate remained undisturbed. The clearance values in milliliters per minute for G, inulin, and p -aminohippuric acid were 40.3 ± 1.8, 49.9 ± 2.8, and 132 ± 14, respectively. The ratio of clearance of G to clearance of inulin was 0.82 ± 0.04 ( P < 0.005), suggesting net reabsorption of G by the renal tubules. The renal cortex/serum ratio for G was 11.9 ± 2.1, and the medulla/serum ratio was 2.7 ± 0.4, indicating greater uptake of G by the cortex. The extraction ratio of p -aminohippuric acid was 0.74 ± 0.03. In contrast, the extraction ratio of G was 0.20 ± 0.03, which was significantly lower than that of inulin (0.30 ± 0.04). It is concluded that the accumulation of G in the cortex was due to tubular reabsorption. Probably some of the reabsorbed G became trapped in the epithelial cells after crossing the luminal membrane, whereas some returned to the circulation.

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Section: Resultsmentioning

confidence: 99%

Renal Extraction of Gentamicin in Anesthetized Dogs

Chiu¹,

Brown²,

Miller³

et al. 1976

Antimicrob Agents Chemother

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show abstract

“…In fact, it has been shown that only the unbound drug fraction in the ISF has the ability to exert antiinfective efficacy, both in vitro and in vivo (31,32,33,34,86,99,184). Clinical examples for the relevance of protein binding were given in an article by Wise (184); these included therapeutic failures with fusidic acid or ceftriaxone in gonorrhoea and the close relationship between the failure of cefoperazone in serious illness and the degree of protein binding.…”

Section: Four Common Misconceptions About Tissue Drug Distributionmentioning

confidence: 99%

Issues in Pharmacokinetics and Pharmacodynamics of Anti-Infective Agents: Distribution in Tissue

Müller

Peña

Derendorf

2004

Antimicrob Agents Chemother

240

201

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“…Table 1 summarizes the extent of plasma protein binding for drugs across various anti-infective drug classes (10). The impact of protein binding on drug efficacy will depend on the extent of the binding, PK properties, and intrinsic activity of the drug (11)(12)(13)(14)(15). In vitro, the impact of protein binding on antimicrobial activity is often investigated through determination of the MIC, time-kill curves, and cell culture assays (13,16).…”

Section: Introductionmentioning

confidence: 99%

Importance of Relating Efficacy Measures to Unbound Drug Concentrations for Anti-Infective Agents

2013

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SUMMARY For the optimization of dosing regimens of anti-infective agents, it is imperative to have a good understanding of pharmacokinetics (PK) and pharmacodynamics (PD). Whenever possible, drug efficacy needs to be related to unbound concentrations at the site of action. For anti-infective drugs, the infection site is typically located outside plasma, and a drug must diffuse through capillary membranes to reach its target. Disease- and drug-related factors can contribute to differential tissue distribution. As a result, the assumption that the plasma concentration of drugs represents a suitable surrogate of tissue concentrations may lead to erroneous conclusions. Quantifying drug exposure in tissues represents an opportunity to relate the pharmacologically active concentrations to an observed pharmacodynamic parameter, such as the MIC. Selection of an appropriate specimen to sample and the advantages and limitations of the available sampling techniques require careful consideration. Ultimately, the goal will be to assess the appropriateness of a drug and dosing regimen for a specific pathogen and infection.

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Influence of Binding on the Pharmacologic Activity of Antibiotics

Cited by 140 publications

References 14 publications

Renal Extraction of Gentamicin in Anesthetized Dogs

Renal Extraction of Gentamicin in Anesthetized Dogs

Issues in Pharmacokinetics and Pharmacodynamics of Anti-Infective Agents: Distribution in Tissue

Importance of Relating Efficacy Measures to Unbound Drug Concentrations for Anti-Infective Agents

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