The influence of bile salts on the distribution of simvastatin in the octanol/buffer system

INTRODUCTION: Distribution coefficient (D) is useful parameter for evaluating drugs permeability properties across biological membranes, which are of importance for drugs bioavailability. Given that bile acids are intensively studied as drug permeation-modifying and -solubilizing agents, the aim of this study was to estimate the influence of sodium salts of cholic (CA), deoxycholic (DCA) and 12-monoketocholic acids (MKC) on distribution coefficient of simvastatin (SV) (lactone [SVL] and acid form [SVA]) which is a highly lipophilic compound with extremely low water solubility and bioavailability. METHODS: LogD values of SVA and SVL with or without bile salts were measured by liquid-liquid extraction in n-octanol/buffer systems at pH 5 and 7.4. SV concentrations in aqueous phase were determined by HPLC-DAD. Chem3D Ultra program was applied for computation of physico-chemical properties of analyzed compounds and their complexes. RESULTS: Statistically significant decrease in both SVA and SVL logD was observed for all three studied bile salts at both selected pH. MKC exerted the most pronounced effect in the case of SVA while there were no statistically significant differences between observed bile salts for SVL. The calculated physico-chemical properties of analyzed compounds and their complexes supported experimental results. CONCLUSIONS: Our data indicate that the addition of bile salts into the n-octanol/buffer system decreases the values of SV distribution coefficient at both studied pH values. This may be the result of the formation of hydrophilic complexes increasing the solubility of SV that could consequently impact the pharmacokinetic parameters of SV and the final drug response in patients

Bile acids and their derivatives as potential modifiers of drug release and pharmacokinetic profiles

Copyright © 2018 Pavlovic, Golocorbin-Kon, Danic, Stanimirov. Bile acids have received considerable interest in the drug delivery research due to their peculiar physicochemical properties and biocompatibility. The main advantage of bile acids as drug absorption enhancers is their ability to act as both drug solubilizing and permeation-modifying agents. Therefore, bile acids may improve bioavailability of drugs whose absorption-limiting factors include either poor aqueous solubility or low membrane permeability. Besides, bile acids may withstand the gastrointestinal impediments and aid in the transporter-mediated absorption of physically complexed or chemically conjugated drug molecules. These biomolecules may increase the drug bioavailability also at submicellar levels by increasing the solubility and dissolution rate of non-polar drugs or through the partition into the membrane and increase of membrane fluidity and permeability. Most bile acid-induced effects are mediated by the nuclear receptors that activate transcriptional networks, which then affect the expression of a number of target genes, including those for membrane transport proteins, affecting the bioavailability of a number of drugs. Besides micellar solubilization, there are many other types of interactions between bile acids and drug molecules, which can influence the drug transport across the biological membranes. Most common drug-bile salt interaction is ion-pairing and the formed complexes may have either higher or lower polarity compared to the drug molecule itself. Furthermore, the hydroxyl and carboxyl groups of bile acids can be utilized for the covalent conjugation of drugs, which changes their physicochemical and pharmacokinetic properties. Bile acids can be utilized in the formulation of conventional dosage forms, but also of novel micellar, vesicular and polymer-based therapeutic systems. The availability of bile acids, along with their simple derivatization procedures, turn them into attractive building blocks for the design of novel pharmaceutical formulations and systems for the delivery of drugs, biomolecules and vaccines. Although toxic properties of hydrophobic bile acids have been described, their side effects are mostly produced when present in supraphysiological concentrations. Besides, minor structural modifications of natural bile acids may lead to the creation of bile acid derivatives with the reduced toxicity and preserved absorption-enhancing activity

Global uptake of carbonyl sulfide (COS) by terrestrial vegetation: Estimates corrected by deposition velocities normalized to the uptake of carbon dioxide (CO2)

COS uptake by trees, as observed under dark/light changes and under application of the plant hormone abscisic acid, exhibited a strong correlation with the CO2 assimilation rate and the stomatal conductance. As the uptake of COS occurred exclusively through the stomata we compared experimentally derived and re-evaluated deposition velocities (V-d; related to stomatal conductance) for COS and CO2. We show that Vd of COS is generally significantly larger than that of CO2. We therefore introduced this attribute into a new global estimate of COS fluxes into vegetation. The new global estimate of the COS uptake based on available net primary productivity data (NPP) ranges between 0.69-1.40 Tg a(-1). However, as a COS molecule is irreversibly split in contrast to CO2 which is released again by respiration processes, we took into account the Gross Primary Productivity (GPP) representing the true CO2 leaf flux the COS uptake has to be related to. Such a GPP based deposition estimate ranged between 1.4-2.8 Tg a(-1) (0.73-1.50 Tg S a(-1)). We believe that in order to obtain accurate global COS sink estimates such a GPP-based estimate corrected by the different deposition velocities of COS and CO2 must be taken into account

Potential Applications of Gliclazide in Treating Type 1 Diabetes Mellitus: Formulation with Bile Acids and Probiotics

© 2017 Springer International Publishing AG A major advancement in therapy of type 1 diabetes mellitus (T1DM) is the discovery of new treatment which avoids and even replaces the absolute requirement for injected insulin. The need for multiple drug therapy of comorbidities associated with T1DM increases demand for developing novel therapeutic alternatives with new mechanisms of actions. Compared to other sulphonylurea drugs used in the treatment of type 2 diabetes mellitus, gliclazide exhibits a pleiotropic action outside pancreatic ß cells, the so-called extrapancreatic effects, such as antiinflammatory and cellular protective effects, which might be beneficial in the treatment of T1DM. Results from in vivo experiments confirmed the positive effects of gliclazide in T1DM that are even more pronounced when combined with other hypoglycaemic agents such as probiotics and bile acids. Even though the exact mechanism of interaction at the molecular level is still unknown, there is a clear synergistic effect between gliclazide, bile acids and probiotics illustrated by the reduction of blood glucose levels and improvement of diabetic complications. Therefore, the manipulation of bile acid pool and intestinal microbiota composition in combination with old drug gliclazide could be a novel therapeutic approach for patients with T1DM