Species differences in drug plasma protein binding

Colclough, Nicola; Ruston, Linette; Wood, J. Matthew; MacFaul, Philip A.

doi:10.1039/c4md00148f

Cited by 58 publications

(41 citation statements)

References 17 publications

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“…The relatively low physiological SA concentrations in rodents of 20 mg/ml, which is half of that observed in rabbits and humans, at least partially explains the inability of rodent sera to serve as substrates for high-level CF-301 activity. While there are undoubtedly other differences in the compositions of rodent and human sera, it is most striking that protein binding, primarily to albumin, is lower in rodents than in humans for most antimicrobials (10,36,37). Binding preferences of up to 1,000-fold for HSA over rodent SA have been reported, and there are distinct structural differences in the binding sites of human and rodent albumins to account for differences in the extent of drug binding (38)(39)(40).…”

Section: Resultsmentioning

confidence: 99%

The Antistaphylococcal Lysin, CF-301, Activates Key Host Factors in Human Blood To Potentiate Methicillin-ResistantStaphylococcus aureusBacteriolysis

Sauve

Raz

Abdelhady

et al. 2019

Antimicrob Agents Chemother

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Bacteriophage-derived lysins are cell-wall-hydrolytic enzymes that represent a potential new class of antibacterial therapeutics in development to address burgeoning antimicrobial resistance. CF-301, the lead compound in this class, is in clinical development as an adjunctive treatment to potentially improve clinical cure rates of Staphylococcus aureus bacteremia and infective endocarditis (IE) when used in addition to antibiotics. In order to profile the activity of CF-301 in a clinically relevant milieu, we assessed its in vitro activity in human blood versus in a conventional testing medium (cation-adjusted Mueller-Hinton broth [caMHB]). CF-301 exhibited substantially greater potency (32 to Ն100-fold) in human blood versus caMHB in three standard microbiologic testing formats (e.g., broth dilution MICs, checkerboard synergy, and time-kill assays). We demonstrated that CF-301 acted synergistically with two key human blood factors, human serum lysozyme (HuLYZ) and human serum albumin (HSA), which normally have no nascent antistaphylococcal activity, against a prototypic methicillin-resistant S. aureus (MRSA) strain (MW2). Similar in vitro enhancement of CF-301 activity was also observed in rabbit, horse, and dog (but not rat or mouse) blood. Two well-established MRSA IE models in rabbit and rat were used to validate these findings in vivo by demonstrating comparable synergistic efficacy with standard-of-care anti-MRSA antibiotics at Ͼ100-fold lower lysin doses in the rabbit than in the rat model. The unique properties of CF-301 that enable bactericidal potentiation of antimicrobial activity via activation of "latent" host factors in human blood may have important therapeutic implications for durable improvements in clinical outcomes of serious antibiotic-resistant staphylococcal infections.

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Section: Resultsmentioning

confidence: 99%

The Antistaphylococcal Lysin, CF-301, Activates Key Host Factors in Human Blood To Potentiate Methicillin-ResistantStaphylococcus aureusBacteriolysis

Sauve

Raz

Abdelhady

et al. 2019

Antimicrob Agents Chemother

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“…A "Hit" was defined as a compound which demonstrated a dose response curve with an IC 50 but also passed multiple and sometimes project specific criteria to rule out artifacts and non-specific inhibitors (e.g. nephelometry 21 measurements>IC 50 , Hill slope >0.5 and <2, activity against other bacterial isozymes, chemical property filters; with FBLG projects X-ray structure or NMR confirmation etc). Of the examples we studied, the properties did not change much in going from Active to Hit (average ∆logD = -0.26 from Active to Hit, discussed in more detail below, Table 2).…”

Section: Analysis Of Hts Actives and Hitsmentioning

confidence: 99%

Trends and Exceptions of Physical Properties on Antibacterial Activity for Gram-Positive and Gram-Negative Pathogens

et al. 2014

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To better understand the difficulties surrounding the identification of novel antibacterial compounds from corporate screening collections, physical properties of ∼3200 antibacterial project compounds with whole cell activity against Gram-negative or Gram-positive pathogens were profiled and compared to actives found from high throughput (HTS) screens conducted on both biochemical and phenotypic bacterial targets. The output from 23 antibacterial HTS screens illustrated that when compared to the properties of the antibacterial project compounds, the HTS actives were significantly more hydrophobic than antibacterial project compounds (typically 2-4 log units higher), and furthermore, for 14/23 HTS screens, the average clogD was higher than the screening collection average (screening collection clogD = 2.45). It was found that the consequences of this were the following: (a) lead identification programs often further gained hydrophobic character with increased biochemical potency, making the separation even larger between the physicochemical properties of known antibacterial agents and the HTS active starting point, (b) the probability of plasma protein binding and cytotoxicity are often increased, and (c) cell-based activity in Gram-negative bacteria was severely limited or, if present, demonstrated significant efflux. Our analysis illustrated that compounds least susceptible to efflux were those which were highly polar and small in MW or very large and typically zwitterionic. Hydrophobicity was often the dominant driver for HTS actives but, more often than not, precluded whole cell antibacterial activity. However, simply designing polar compounds was not sufficient for antibacterial activity and pointed to a lack of understanding of complex and specific bacterial penetration mechanisms.

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“…When 10 ug/mL of cefovecin (a concentration used in other in vitro studies 3,17 ) was incubated in plasma, the median (range) PPB% in the marsupial species ranged from 11.1% ([4.1-20.4%], Tasmanian Devil) to 36.4% ([35.0-38.3%], red kangaroo), while it was 95.6% (94.9-96.6%) in the horse. 27,28 Differences in the structure of the proteins in the plasma of those species tested here were not investigated in this study. 26 Interspecies differences in PPB can be attributable to the differences in albumin amino acid sequence, which affects binding capacity.…”

Section: Discussionmentioning

confidence: 97%

“…26 Interspecies differences in PPB can be attributable to the differences in albumin amino acid sequence, which affects binding capacity. 27,28 Differences in the structure of the proteins in the plasma of those species tested here were not investigated in this study.…”

Section: Discussionmentioning

confidence: 97%

In vitro binding of cefovecin to plasma proteins in Australian marsupials and plasma concentrations of cefovecin following single subcutaneous administration to koalas (Phascolarctos cinereus)

2019

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Background Cefovecin has a long duration of antibiotic activity in cats and dogs, somewhat attributable to its high plasma protein binding. Aims To determine the cefovecin binding to plasma proteins in vitro in selected Australian marsupials and to quantify the change in cetovecin concentration over time following subcutaneous injection in koalas. Methods and results Various cefovecin concentrations were incubated with plasma and quantified using HPLC. The median (range) bound percentages when 10 μg/mL of cefovecin was incubated with plasma were 11.1 (4.1–20.4) in the plasma of the Tasmanian devil, 12.7 (5.8–17.3) in the koala, 18.9 (14.6–38.0) in the eastern grey kangaroo, 16.9 (15.7–30.2) in the common brush‐tailed possum, 37.6 (25.3–42.3) in the eastern ring‐tailed possum and 36.4 (35.0–38.3) in the red kangaroo, suggesting that cefovecin may have a shorter duration of action in these species than in cats and dogs. Cefovecin binding to plasma proteins in thawed, frozen equine plasma was also undertaken for assay quality control and the median (range) plasma protein binding (at 10 μg/mL) was 95.6% (94.9–96.6%). Cefovecin was also administered to six koalas at 8 mg/kg subcutaneously and serial blood samples were collected at 3, 6, 24, 48, 72, 96 h thereafter. Cefovecin plasma concentrations were not quantifiable in four koalas and in the other two, the mean plasma concentration at t = 3 h was 1.04 ± 0.01 μg/mL. Conclusion Because of the limited pharmacokinetic data generated, no further pharmacokinetic analysis was performed; however, a single injected bolus of cefovecin is likely to have a short duration of action in koalas (hours, rather than days).

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Species differences in drug plasma protein binding

Abstract: Comparison of the human plasma protein binding data for a variety of drug discovery compounds indicates that compounds tend to be slightly more bound to human plasma proteins, than compared to plasma proteins from rats, dogs or mice.

Cited by 58 publications

References 17 publications

The Antistaphylococcal Lysin, CF-301, Activates Key Host Factors in Human Blood To Potentiate Methicillin-ResistantStaphylococcus aureusBacteriolysis

The Antistaphylococcal Lysin, CF-301, Activates Key Host Factors in Human Blood To Potentiate Methicillin-ResistantStaphylococcus aureusBacteriolysis

Trends and Exceptions of Physical Properties on Antibacterial Activity for Gram-Positive and Gram-Negative Pathogens

In vitro binding of cefovecin to plasma proteins in Australian marsupials and plasma concentrations of cefovecin following single subcutaneous administration to koalas (Phascolarctos cinereus)

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