ABSTRACT
In this study, we investigated the ability of the general anesthetic propofol (PR) to form inclusion complexes with modified ß-cyclodextrins, including sulfobutylether-ß-cyclodextrin (SBEßCD) and hydroxypropyl-ß-cyclodextrin (HPßCD). The PR/SBEßCD and PR/HPßCD complexes were prepared and characterized, and the blood-brain barrier (BBB) permeation potential of the formulated PR was examined in vivo for the purpose of controlled drug delivery. The PR/SBEßCD complex was found to be more stable in solution with a minimal degradation constant of 0.25 h-1, a t1/2 of 2.82 h, and a Kc of 5.19 × 103 M-1 and revealed higher BBB permeability rates compared with the reference substance (PR-LIPURO) considering the calculated brain-to-blood concentration ratio (logBB) values. Additionally, the diminished PR binding affinity to SBEßCD was confirmed in molecular dynamics simulations by a maximal Gibbs free energy of binding (ΔGbind = -18.44 kcal·mol-1), indicating the more rapid PR/SBEßCD dissociation. Overall, the results demonstrated that SBEßCD has the potential to be used as a prospective candidate for drug delivery vector development to improve the pharmacokinetic and pharmacodynamic properties of general anesthetic agents at the BBB level.
Subject(s)
Anesthetics, Intravenous/administration & dosage , Blood-Brain Barrier/metabolism , Propofol/administration & dosage , beta-Cyclodextrins/administration & dosage , 2-Hydroxypropyl-beta-cyclodextrin , Anesthetics, Intravenous/chemistry , Anesthetics, Intravenous/pharmacokinetics , Animals , Delayed-Action Preparations/chemistry , Drug Delivery Systems , Mice, Inbred C57BL , Mice, Transgenic , Molecular Dynamics Simulation , Propofol/chemistry , Propofol/pharmacokinetics , beta-Cyclodextrins/chemistry , beta-Cyclodextrins/pharmacokineticsABSTRACT
The objective of the present investigation was to study the ability of sulfobutylether-ß-cyclodextrin (SBEßCD) to form an inclusion complex with sevoflurane (SEV), a volatile anesthetic with poor water solubility. The inclusion complex was prepared, characterized and its cellular toxicity and blood-brain barrier (BBB) permeation potential of the formulated SEV have also been examined for the purpose of controlled drug delivery. The SEV-SBEßCD complex was nontoxic to the primary brain microvascular endothelial (pEND) cells at a clinically relevant concentration of sevoflurane. The inclusion complex exhibited significantly higher BBB permeation profiles as compared with the reference substance (propranolol) concerning calculated apparent permeability values (Papp). In addition, SEV binding affinity to SBEßCD was confirmed by a minimal Gibbs free energy of binding (ΔGbind) value of -1.727 ± 0.042 kcal·mol-1 and an average binding constant (Kb) of 53.66 ± 9.24 mM indicating rapid drug liberation from the cyclodextrin amphiphilic cavity.
Subject(s)
Anesthetics, Inhalation/metabolism , Delayed-Action Preparations , Methyl Ethers/metabolism , beta-Cyclodextrins/metabolism , Anesthetics, Inhalation/chemistry , Anesthetics, Inhalation/pharmacology , Animals , Blood-Brain Barrier/cytology , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/metabolism , Brain/blood supply , Brain/cytology , Brain/drug effects , Brain/metabolism , Capillary Permeability , Cell Survival/drug effects , Drug Compounding , Endothelial Cells/cytology , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Methyl Ethers/chemistry , Methyl Ethers/pharmacology , Mice , Molecular Docking Simulation , Primary Cell Culture , Propranolol/metabolism , Propranolol/pharmacology , Sevoflurane , beta-Cyclodextrins/chemistry , beta-Cyclodextrins/pharmacologyABSTRACT
Although food-drug interactions have been studied extensively in recent years, in the light of the complex nature of these interactions general guideline for clinical practice can not be given. Drug interactions with food (containing multivalent metal ions or protein) can have an influence on drug absorption with widely variety of mechanism, resulting in changes in both the rate and extent of bioavailability. Food-drug interaction can be important in the clinical practice. Studies of the interaction between food/juice and fluoroquinolones have produced conflicting results. A number of studies give evidence that fluoroquinolones forming slightly soluble complex with metal ions of food show reduced bioavailability. In the same time, concurrent ingestion of food/ juice with fluoroquinolones has been shown not to interfere with their absorption to a clinically significant degree.
Subject(s)
Fluoroquinolones/pharmacokinetics , Food-Drug Interactions/physiology , Intestinal Absorption/physiology , Animals , Anti-Bacterial Agents/pharmacokinetics , Beverages , Biological Availability , Humans , Kinetics , MilkABSTRACT
As fluoroquinolone antibiotics are known to interact with foods containing multivalent ions, dairy products represent a risk for less than optimal absorption of them. A number of studies give evidence that fluoroquinolones forming slightly soluble complexes with metal ions of foods show reduced bioavailability. Our aim was to investigate the in vitro dissolution profile of a marketed ciprofloxacin (CPFX) containing tablet in aqueous and low fat milky mediums. For our experiments three various pH values were chosen to represent the circumstances of the gastrointestinal tract. Solid phase extraction (SPE) sample preparation followed by high performance liquid chromatography coupled mass spectrometry (LC-MS) technique was used to determine the amount of free CPFX. According to our results the presence of milk decreases the amount of bioavailable CPFX.
