Effects of Magnesium, Calcium, and Aluminum Chelation on Fluoroquinolone Absorption Rate and Bioavailability: A Computational Study

Abstract

Fluoroquinolones (FQs) are a widespread class of broad-spectrum antibiotics prescribed as a first line of defense, and, in some cases, as the only treatment against bacterial infection. However, when administered orally, reduced absorption and bioavailability can occur due to chelation in the gastrointestinal tract (GIT) with multivalent metal cations acquired from diet, coadministered compounds (sucralfate, didanosine), or drug formulation. Predicting the extent to which this interaction reduces in vivo antibiotic absorption and systemic exposure remains desirable yet challenging. In this study, we focus on quinolone interactions with magnesium, calcium and aluminum as found in dietary supplements, antacids (Maalox) orally administered therapies (sucralfate, didanosine). The effect of FQ–metal complexation on absorption rate was investigated through a combined molecular and pharmacokinetic (PK) modeling study. Quantum mechanical calculations elucidated FQ–metal binding energies, which were leveraged to predict the magnitude of reduced bioavailability via a quantitative structure–property relationship (QSPR). This work will help inform clinical FQ formulation design, alert to possible dietary effects, and shed light on drug–drug interactions resulting from coadministration at an earlier stage in the drug development pipeline.

Ciprofloxacin Release and Corrosion Behaviour of a Hybrid PEO/PCL Coating on Mg3Zn0.4Ca Alloy

“…Higher CIP release from porous PCL film on a glass substrate is observed. The loaded PCL film reveals a burst release of ~50% of the entire load during the first 2 h of immersion followed by the release of the remaining load (up to 80–97% of the total) over 48 h. However, in the case of HCC + CIP, a gradual release over time is observed, with only 64% of the load released over the period of 240 h. The possible reason of this may be associated with the fact that Mg 2+ and Ca 2+ cations, liberated from the HHC and the substrate, are chelating with CIP 0 (zwitterionic form, Figure S3 ) leading to the formation of insoluble chelates in the physiological medium [ 19 ] and reducing the CIP release. This observation is in good agreement with other reports where the complexation of different cations present in physiological media with CIP was shown, reducing the bioavailability of the drug [ 20 , 21 ].…”

“…This suggests that CIP presents an inhibiting effect on the corrosion behaviour of PEO-coated Mg. In this work, this effect could be associated with the formation of insoluble chelates such as Mg/Ca-CIP o [ 19 ] ( Figure S3 ) that could precipitate in the cracks and pores of the PEO coating blocking the access of the corrosive species of the medium. The complexation of these compounds is predicted to be thermodynamically favourable at neutral pH as it was reported in works of pharmacokinetics of the fluoroquinolone group to which CIP belongs [ 12 , 32 ].…”

Preliminary Studies of Antimicrobial Activity of New Synthesized Hybrids of 2-Thiohydantoin and 2-Quinolone Derivatives Activated with Blue Light

“…Besides, transport into the cell is connected with the size of the molecule—e.g., a quinolone molecule chelated with Ca 2+ or Mg 2+ . Such a complex molecule cannot enter the cell because of the bulky size [ 51 ]. The effect of greater sensitivity of Gram-positive bacteria to the examined compounds is also consisted with those reported for other 2-thiohydantoins derivatives.…”

New Efforts toward Aminothiazolylquinolones with Multitargeting Antibacterial Potential

“…It is revealed that the bacterial resistance to quinolones might be driven by an increase in the expression of efflux pumps and the decreases of certain outer membrane proteins such as porins as well as the residue mutations of target enzymes in the quinolone resistance determining region, which especially play a vital role in preventing the formation of the ion bridge with 3-carboxyl and 4-carbonyl groups to render quinolones with ineffective antibacterial behavior . The increasingly growing multidrug resistance reflects a global issue creating superbugs difficult to treat. , Moreover, some side effects such as the metal chelation and the retroaction with alkaline drugs also result from the 3-carboxyl group of quinolones. − It is of great urgency to develop novel therapeutic strategies, antibacterial drugs with high biosafety, and even targets to counteract the growing multidrug resistance in animal husbandry. , …”