Interaction Of Fluoroquinolones Research Articles

Effect of Methyl-\u03b2-Cyclodextrin on the Interaction of Fluoroquinolones with Human Serum Albumin

—The influence of the structure of fluoroquinolones (on the example of ciprofloxacin and levofloxacin) and their complexation with methyl-β-cyclodextrin on the interaction of the drug with human serum albumin was studied. It was found that the binding of the drug molecule with albumin is significantly affected by the structure of fluoroquinolone, as well as the presence of methyl-β-cyclodextrin. It was discovered that of the two fluoroquinolones, the more hydrophobic ciprofloxacin molecule interacts more strongly with the protein, using circular dichroism and fluorescence spectroscopy methods. It has also been shown that binding of albumin to the drug causes quenching of protein fluorescence, and this effect is more pronounced for ciprofloxacin. The complexation of fluoroquinolones with methyl-β-cyclodextrin leads to a change in the interaction of fluoroquinolones with the protein: in the case of complexes, more pronounced interactions are observed for levofloxacin. The results obtained will help to bring the use of fluoroquinolones to a new level in clinical practice, by creating new highly effective drugs with improved properties.

Interaction of Fluoroquinolones in Their Different Prototropic States with DNA: Diversity in the Nature of Binding and the Role of External Chemical Stimulus on Drug Displacement

AbstractHere we have explored several aspects on the interaction of fluoroquinolone (fq) drugs with one of their potential biological targets, DNA, using spectroscopic techniques. After many scrutinies on whether the fqs can target DNA itself, we found that some earlier studies first detected norfloxacin to bind DNA, and the binding occurs primarily via conversion of the zwitterionic (nfx±) to cationic form (nfx+). Here we have selectively chosen some fq drugs together, namely, norfloxacin, ciprofloxacin, ofloxacin, and moxifloxacin with diversity in molecular structures to perceive a comprehensive scenario on the fq‐DNA interaction. The following aspects are focused on: characteristics of fq±‐DNA interaction, prevalence of fq± to fq+ conversion during binding, association of the fq+s with DNA, and the mode of binding of the fqs. Considering the issue of fq± to fq+ conversion and hence the active participation of fq+s in DNA binding, here we have specifically assessed the interaction feature of fq+s with DNA, where potential binding has been detected. The present study has identified that fq‐DNA association has some characteristics that are in general similar for all the fqs, and some are specific to the particular fq drug. Therefore, although the fqs play similar role as antibiotic involving bacterial gyrase, their individual association with DNA is somewhat diverse. Additionally, we have demonstrated dislodging of the bound drug (nfx± and nfx+) from DNA by using an anionic surfactant.

Copper(II)–fluoroquinolone complexes with anti-Trypanosoma cruzi activity and DNA binding ability

Copper(II) complexes of fluoroquinolone antibacterial agents levofloxacin (LEV) and sparfloxacin (SPAR), containing or not a nitrogen donor heterocyclic ligand, 2,2'-bipyridine (bipy) or 1,10-phenathroline (phen), were prepared and characterized. The complexes are of the type [CuCl(2)(H(2)O)(L)], [CuCl(bipy)(L)]Cl and [CuCl(2)(phen)(L)], where L=LEV or SPAR. The data suggest that LEV and SPAR act as zwitterionic bidentade ligands coordinated to Cu(II) through the carboxylate and ketone oxygen atoms. The electron paramagnetic resonance spectra of the [CuCl(bipy)(L)]Cl and [CuCl(2)(phen)(L)] complexes (L=LEV and SPAR) in aqueous and DMSO solutions indicate mixture of mononuclear and binuclear forms. The Cu(II) complexes, together with the corresponding ligands, were evaluated for their trypanocidal activity in vitro against Trypanosoma cruzi, the causative agent of Chagas disease. The assays performed against bloodstream trypomastigotes showed that all complexes were more active than their corresponding ligands. Complexes [CuCl(2)(phen)(LEV)] and [CuCl(2)(phen)(SPAR)] were revealed, among all studied compounds, to be the most active with IC(50)=1.6 and 4.7μM, respectively, both presenting a superior effect than benznidazole. The interactions of fluoroquinolones and their Cu(II) complexes with calf-thymus DNA were investigated. These compounds showed binding properties towards DNA, with moderated binding constants values, suggesting that this structure may represent a parasite target.

Binding characteristics of fluoroquinolones to synthetic levodopa melanin.

To define the binding characteristics of fluoroquinolones to synthetic levodopa melanin, the binding of various drugs, including levofloxacin and ofloxacin, and positive controls (timolol and chloroquine), was investigated in-vitro. The affinity and capacity of the drug binding were calculated by Langmuir's adsorption isotherm. The affinity constant (K) and the binding capacity (r(max)) of levofloxacin were similar to those of timolol and much lower than those of chloroquine. Racemic ofloxacin and its enantiomers showed similar K and r(max), suggesting that the binding lacked stereoselectivity. The binding experiment with levofloxacin derivatives indicated that the basic nitrogen atom at position 7 of the quinolone ring, but not carboxyl group at position 3, would play a critical role in the interaction of fluoroquinolones with melanin. The melanin-drug complexes of levofloxacin and chloroquine were washed with neutral phosphate buffer, ethanol and 1 M HCl solution to explain the nature of the interaction of melanin with the drugs. Electrostatic forces mainly participate in the formation of the chloroquine-melanin complex, whereas van der Waals' and hydrophobic interactions are involved in the levofloxacin-melanin complex in addition to electrostatic forces. The interactions of various fluoroquinolones such as norfloxacin, enoxacin, sparfloxacin, ciprofloxacin and lomefloxacin with melanin were also studied. The results showed that the relative K value was: chloroquine approximately ciprofloxacin, sparfloxacin >/= lomefloxacin > timolol, levofloxacin approximately enoxacin, norfloxacin, and that the relative r(max) value was: norfloxacin, enoxacin >/= chloroquine, sparfloxacin > levofloxacin, ciprofloxacin, timolol, lomefloxacin. The fluoroquinolones vary in their affinity and capacity to bind with melanin, and ciprofloxacin and sparfloxacin showed a stronger interaction with melanin than the other fluoroquinolones studied.

Interaction of fluoroquinolones and certain ionophores in broilers: effect on blood levels and hepatic cytochrome p450 monooxygenase activity.

The concomitant administration to broilers of ionophore coccidiostats and certain chemotherapeutic agents may cause deleterious interactions, with toxicosis and death as possible sequelae. In this study, co-administration of the ionophore monensin was not shown to alter blood levels of enrofloxacin or norfloxacin. In addition, exposure to lasalocid was not shown to change blood levels of enrofloxacin. However, norfloxacin + lasalocid co-administration induced aminopyrine N-demethylase (AD) activity by day 5 after the last administration of norfloxacin, and induced a rise of norfloxacin levels in the blood. This rise of blood norfloxacin levels after co-administration of norfloxacin + lasalocid implies that lower levels of norfloxacin could be administered in birds also receiving lasalocid.

Possible interaction of fluoroquinolones with the benzodiazepine‐GABAA‐ receptor complex.

1. The possible involvement of the benzodiazepine (BZD)-GABAA-receptor complex in mediating CNS stimulatory effects of fluoroquinolones was tested in vitro, in a binding inhibition assay and in vivo, in a clinical drug interaction study using electro-encephalogram (EEG) monitoring. 2. The specific binding of [3H]-flunitrazepam to rat synaptic brain membranes was inhibited by various fluoroquinolones in a concentration-dependent manner. 3. Ofloxacin had CNS-stimulating effects as revealed by the EEG which were slightly augmented by flumazenil but reversed by coadministration of midazolam. 4. In conclusion, our findings suggest that clinically observed CNS adverse effects of fluoroquinolones could be mediated at least in part through interaction with the BZD-GABAA-receptor complex and may be controlled by BZD agonist administration.