Physicochemical profile of macrolides and their comparison with small molecules

Stepanić, Višnja; Žiher, Dinko; Gabelica-Marković, Vesna; Jelić, Dubravko; Nunhuck, Shenaz; Valkó, Klára; Koštrun, Sanja

doi:10.1016/j.ejmech.2011.11.016

Cited by 32 publications

(30 citation statements)

References 53 publications

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“…They used calculated physicochemical properties. In this study, the measured physicochemical and biomimetic properties are compared with marketed drugs [36] and macrolides [41]. The marketed drugs were divided into inhaled and CNS group.…”

Section: Resultsmentioning

confidence: 99%

Application of biomimetic HPLC to estimate lipophilicity, protein and phospholipid binding of potential peptide therapeutics

Valkó¹,

Ivanova-Berndt²,

Beswick³

et al. 2018

ADMET DMPK

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<p class="ADMETabstracttext">Peptide therapeutics are new modalities offering several challenges to drug discovery. They are generally less stable and permeable in vivo. The characterization of their lipophilicity cannot be carried out using the traditional in silico or wet octanol/water partition coefficients. The prediction of their in vivo distribution and permeability is also challenging. In this paper, it is demonstrated that the biomimetic properties such as lipophilicity, protein and phospholipid binding can be easily assessed by HPLC using chemically bonded protein and immobilized artificial membrane (IAM) stationary phases. The obtained properties for a set of potential therapeutic peptides with 3 to 33 amino acids have been analysed and it was found that similar characteristics of the properties could be observed as for small molecule drugs. The albumin binding showed correlation with their measured lipophilicity on the C-18 stationary phase with acidic peptides showing stronger than expected albumin binding. The (IAM) chromatography revealed peptide membrane affinity, which was stronger for positively charged peptides (containing arginine) and showed correlation to the alpha-1-acid glycoprotein (AGP) binding, which was also stronger for positively charged compounds. The in vivo volume of distribution and drug efficiency of the peptides have been estimated using the models developed for small molecules. One of the candidate linear peptides has been assessed in various cellular and in vivo assays and the results have confirmed the estimated cell partition and brain to plasma ratio. It can be demonstrated, that up to 21 amino acids, the peaks of the peptides obtained on the protein phase were symmetrical and narrow. The interaction of larger peptides with the protein stationary phases resulted in wide peaks showing multiple equilibrium processes with slow kinetics during chromatography. The larger peptides showed narrow and symmetrical peaks on the IAM column enabling the quantification of peptide - cell membrane interactions.</p>

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Section: Resultsmentioning

confidence: 99%

Application of biomimetic HPLC to estimate lipophilicity, protein and phospholipid binding of potential peptide therapeutics

Valkó¹,

Ivanova-Berndt²,

Beswick³

et al. 2018

ADMET DMPK

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“…The concentrations of Σerythromycin (1.6-22.7 ng/L) were one order of magnitude greater than roxithromycin (0.1-1 ng/L). Macrolides are large complex molecules with a number of stereocenters, and are widely used in human disease control (Murata et al, 2011;Stepanić et al, 2012). The relatively low concentration of macrolides in the aquatic environment was due to their high hydrophobicity and strong sorption affinities to sediments (Chen and Zhou, 2014), although pharmaceutical concentrations were not determined in SPM samples due to low SPM concentrations.…”

Section: Concentrations Of Dissolved Pharmaceuticals In the Yangtze Ementioning

confidence: 99%

Tidal impact on the dynamic behavior of dissolved pharmaceuticals in the Yangtze Estuary, China

Zhao

Zhou

Zhang

2015

Science of The Total Environment

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“…It has a high cellular accumulation, particularly in phagocytes. Subsequently, high concentrations of azithromycin are targeted to sites of infection and inflammation …”

Section: The Role Of Macrolides In Non‐cf Bronchiectasismentioning

confidence: 99%

A review of non‐cystic fibrosis bronchiectasis in children with a focus on the role of long‐term treatment with macrolides

Boustany¹,

Gachelin²,

Colomban³

et al. 2019

Pediatric Pulmonology

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Bronchiectasis is a rare chronic airway disease arising from several respiratory and systemic diseases. The grade of evidence for specific treatment of childhood bronchiectasis unrelated to cystic fibrosis (CF) is low with very few randomized controlled trials. Treatment has been based mainly on evidence from studies in adults with non-cystic fibrosis bronchiectasis and patients with cystic fibrosis. Recently, longterm treatment with macrolides has been proposed. These molecules offer the advantage of anti-inflammatory and immunomodulatory properties in addition to their antibacterial properties. A total of three randomized double-blind placebo-controlled trials conducted in adults showed that macrolides taken for 6-12 months led to a significant reduction in exacerbation rates. Only one long-term, randomized doubleblind placebo-controlled trial was conducted in the pediatric population. It showed that azithromycin administered weekly for up to 24 months reduced pulmonary exacerbations. Further randomized controlled studies are needed to determine the optimal dose and duration of treatment with macrolides. The clinical profile of children who would benefit from this treatment also needs to be determined. K E Y W O R D S macrolides, non-cystic-fibrosis bronchiectasis, pulmonary exacerbations

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Physicochemical profile of macrolides and their comparison with small molecules

Cited by 32 publications

References 53 publications

Application of biomimetic HPLC to estimate lipophilicity, protein and phospholipid binding of potential peptide therapeutics

Application of biomimetic HPLC to estimate lipophilicity, protein and phospholipid binding of potential peptide therapeutics

Tidal impact on the dynamic behavior of dissolved pharmaceuticals in the Yangtze Estuary, China

A review of non‐cystic fibrosis bronchiectasis in children with a focus on the role of long‐term treatment with macrolides

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