Absorption-Enhancing Effects of Bile Salts (original) (raw)
Related papers
The Use of Bile Salt Micelles for the Prediction of Human Intestinal Absorption
Journal of pharmaceutical sciences, 2016
Human intestinal absorption (HIA) will dictate biopharmaceutical performance through its influence on absorption, distribution, metabolism, and elimination and can vary significantly depending upon the nature of the compound under consideration. In this study, an in vitro assay method is proposed for the prediction of HIA through the measurement of drug solubility in an aqueous phase containing micellar bile salt, namely sodium deoxycholate. A series of twenty compounds, displaying a range of physicochemical properties and known HIA values, were analyzed using UV spectroscopy to determine a solubilization ratio for each compound. A micelle/water partition coefficient (Kxm/a) was calculated and then used to develop an equation through simple linear regression; logit HIA = -0.919 + 0.4618 logKxm/a (R(2) = 0.85). From this equation, a value for % HIA was determined which compared well with literature. Furthermore, 4 additional drugs were then analyzed using the developed equation and f...
Il Farmaco, 2005
The objective of the present investigation was to evaluate an oral 'drug delivery' approach, which involves co-administration of absorption enhancers (AEs). The representative low permeable hydrophilic (biopharmaceutic classification system (BCS) Class III) drugs used in the study comprised of cefotaxime sodium and ceftazidime pentahydrate, whereas low permeable lipophilic (BCS Class IV) drugs include cyclosporin A and lovastatin. AEs from three different chemical classes, namely, medium chain fatty acids (sodium caprylate and caprate), cyclodextrins (b-cyclodextrin, hydroxypropyl b-cyclodextrin) and bile salts (sodium cholate and deoxycholate) were evaluated for absorption enhancement efficacy, mechanism of action and toxicity using in vitro everted intestinal sac model. These AEs were found to enhance intestinal permeability of drugs from 2-to 27-fold. Light microscopy studies of intestinal sac incubated with AEs for 120 min revealed morphological changes in absorptive mucosa and rank order of toxicity were cyclodextrins > bile salts ≅ medium chain fatty acids. Fluorescence polarization studies indicated that brush bordered membrane vesicles labeled with lipophilic (DPH, 12AS) and hydrophilic dyes (ANS), when treated with AEs exhibited concentration and time dependent decrease in fluorescence polarization. Total protein released in presence of AEs was more than control but considerably less than EDTA (0.58% w/v), which is known to cause toxic release of proteins from cell. Overall, AEs were found to significantly enhance drug permeability by decreasing lipid membrane fluidity and/or interacting with hydrophilic domains of membrane, and has the potential to improve oral delivery.
International Journal of Pharmaceutics, 1994
The present work deals with the effects of bile salts on absorption. It has previously been demonstrated that although they are surfactants, these salts are not able to disrupt the aqueous diffusion layer which effectively limits the absorption of the lipophilic compounds. They exhibit less ability to solubilize in their micelles when they are perfused only in the presence of the tested compounds. The present study was carried out with two types of bile salts-sodium taurocholate and sodium glycocholate-along with other compounds naturally occurring in vivo, such as lecithin and sodium oleate. In this way the hypothesis that an intrinsic mechanism is involved in promoting the effect of bile salts on absorption was assessed by simulating a physiological environment, which always shows mixed micelles of bile salts with phospholipids and fat. Correlations between absorption and lipophilicity parameters are useful for indirect quantification of this phenomenon. The enhancer effect of bile salts on the absorption of lipophilic compounds may be due to their effective absorption in the gut, which helps the disintegration of the micelles. Despite the fact that the characteristics of natural surfactants are not as good as those of synthetic surfactants for promoting absorption, a consideration of all their properties can explain all the features reported.
Biophysical Chemistry, 2001
The objective of this study was to develop non-invasive spectroscopic methods to quantify the partition coefficients of two -blockers, atenolol and nadolol, in aqueous solutions of bile salt micelles and to assess the effect of lecithin on the partition coefficients of amphiphilic drugs in mixed bile saltrlecithin micelles, which were used as a simple Ž. model for the naturally occurring mixed micelles in the gastrointestinal tract. The partition coefficients K at p 25.0" 0.1ЊC and at 0.1 M NaCl ionic strength were determined by spectrofluorimetry and by derivative spectrophotometry, by fitting equations that relate molar extinction coefficients and relative fluorescence intensities to the Ž. partition constant K. Drug partition was controlled by the: i drug properties, with the more soluble drug in water p Ž. atenolol exhibiting smaller values of K , and with both drugs interacting more extensively in the protonated form; p Ž. and by ii the bile salt monomers, with the dihydroxylic salts producing larger values of K for the -blockers, and p with glycine conjugation of the bile acid increasing the values of K for the -blockers. Addition of lecithin to bile p salt micelles decreases the values of K of the -blockers. Mixed micelles incorporate hydrophobic compounds due p to their large size and the fluidity of their core, but amphiphilic drugs, for which the interactions are predominantly polarrelectrostatic, are poorly incorporated in mixed micelles of bile saltsrlecithin.
Biomedical chromatography : BMC, 2016
Understanding intestinal absorption for pharmaceutical compounds is vital to estimate bioavailability and therefore the in vivo potential of a drug. This study considers the application of micellar liquid chromatography (MLC) to predict passive intestinal absorption with a selection of model compounds. MLC is already known to aid prediction of absorption using simple surfactant systems however, with this study the focus was on the presence of a more complex, bile salt surfactant, as would be encountered in the in vivo environment. As a result, MLC using a specific bile salt has been confirmed as an ideal in vitro system to predict the intestinal permeability for a wide range of drugs, through the development of a quantitative partition-absorption relationship. MLC offers many benefits including environmental, economic, time-saving and ethical advantages compared with the traditional techniques employed to obtain passive intestinal absorption values.
Molecular Pharmaceutics, 2013
The oral bioavailability of poorly water-soluble drugs (PWSD) is often significantly enhanced by coadministration with lipids in food or lipid-based oral formulations. Coadministration with lipids promotes drug solubilization in intestinal mixed micelles and vesicles, however, the mechanism(s) by which PWSD are absorbed from these dispersed phases remain poorly understood. Classically, drug absorption is believed to be a product of the drug concentration in free solution and the apparent permeability across the absorptive membrane. Solubilization in colloidal phases such as mixed micelles increases dissolution rate and total solubilized drug concentrations, but does not directly enhance (and may reduce) the free drug concentration. In the absence of changes to cellular permeability (which is often high for lipophilic, PWSD), significant changes to membrane flux are therefore unexpected. Realizing that increases in effective dissolution rate may be a significant driver of increases in drug absorption for PWSD, we explore here two alternate mechanisms by which membrane flux might also be enhanced: (1) collisional drug absorption where drug is directly transferred from lipid colloidal phases to the absorptive membrane, and (2) supersaturation-enhanced drug absorption where bile mediated dilution of lipid colloidal phases leads to a transient increase in supersaturation, thermodynamic activity and absorption. In the current study, collisional uptake mechanisms did not play a significant role in the absorption of a model PWSD, cinnarizine, from lipid colloidal phases. In contrast, bile-mediated dilution of model intestinal mixed micelles and vesicles led to drug supersaturation. For colloids that were principally micellar, supersaturation was maintained for a period sufficient to promote absorption. In contrast, for primarily vesicular systems, supersaturation resulted in rapid drug precipitation and no increase in drug absorption. This work suggests that ongoing dilution by bile in the gastrointestinal tract may invoke supersaturation in intestinal colloids and promote absorption, and thus presents a new mechanism by which lipids may enhance the oral absorption of PWSD.
British Journal of Pharmacology
1 The potential of bile salts to improve the enteral absorption of octreotide, an orally active somatostatin analogue, was investigated by a combination of in vitro, in situ and in vivo experiments. 2 Incorporation of octreotide into lipid monolayers (as measured by area increase of the monolayer at constant surface pressure using a Langmuir-Blodgett trough set-up) depended on the type of bile salt used for monolayer pre-treatment. Addition of 20 gM octreotide to the subphase containing 20 gM of the dihydroxylated bile salt ursodeoxycholate (UDCA) causes a 9% increase in area, whereas addition of octreotide to the subphase containing the 7a-enantiomer of UDCA, chenodeoxycholate (CDCA), resulted in an area increase of the lipid monolayer of 20%. Area increase by octreotide alone was not significantly different from the increase of octreotide and UDCA in combination. 3 CDCA and UDCA in combination with octreotide increased the permeability of liposomal membranes for rubidium ions, whereas octreotide alone did not significantly change the permeability. This indicates membrane distortion as a possible cause for the enhanced absorption of octreotide by bile salts. 4 In polarized Caco-2 cell monolayers octreotide exhibited a permeation coefficient of 0.008 + 0.004 cm h-'. Addition of 0.2-1% of UDCA to the apical incubation medium had no significant effect upon the permeation coefficient. In contrast, 0.2-1% CDCA in the incubation medium resulted in a significant increase (P<0.05) of the monolayer permeability of octreotide (0.015-0.037 cm h-').
International Journal of Pharmaceutics, 2012
The assessment of in vivo drug absorption with in vitro permeability models demands the use of transport media with surface acting compounds. With the aim to establish their influence on in vitro permeability of 30 drugs through Caco-2 monolayers, cell vitality/integrity and micellar drug entrapment, taurocholate/lecithin (NaTC/Leci) and pig crude bile were applied. Drug permeabilities were correlated to fraction of drugs absorbed and appropriate NaTC/Leci and bile concentrations were proposed to simulate fasted/fed conditions in vitro (bile in the concentration range 1-5 v/v% or 0.2/0.05 mM NaTC/Leci for fasted; 10 v/v% bile or 3/0.75 mM NaTC/Leci for fed conditions) without detrimental effects on monolayer integrity/vitality (NaTC/Leci was more toxic than bile). Surfactants exerted different affinities for drugs; free drug concentration (c free) of some was significantly lowered only by bile, while for the others NaTC/Leci and bile significantly diminished c free. For some substances NaTC/Leci and bile significantly increased their permeabilities (i.e. more than 3-times) in spite of profound c free decrease indicating the existence of an alternative absorption mechanism. Based on these data, the impact of bile on in vitro drug permeability and micellar drug entrapment cannot be adequately simulated by NaTC/Leci, because their effects on drug absorption differ.
Colloids and Surfaces B: Biointerfaces, 2023
Formulating poorly soluble drugs with polymers in the form of solid dispersions has been widely used for improving drug dissolution. Endogenous surface-active species present in the gut, such as bile salts, lecithin and other phospholipids, have been shown to play a key role in facilitating lipids and poorly soluble drugs solubilisation in the gut. In this study, we examined the possible occurrence of interactions between a model bile salt, sodium taurocholate (NaTC), and model spray dried solid dispersions comprising piroxicam and Hydroxypropyl Methylcellulose (HPMC), a commonly used hydrophilic polymer for solid dispersion preparation. Solubility measurements revealed the good solubilisation effect of NaTC on the crystalline drug, which was enhanced by the addition of HPMC, and further boosted by the drug formulation into solid dispersion. The colloidal behaviour of the solid dispersions upon dissolution in biorelevant media, with and without NaTC, revealed the formation of NaTC-HPMC complexes and other mixed colloidal species. Cellular level drug absorption studies obtained using Caco-2 monolayers confirmed that the combination of drug being delivered by solid dispersion and the presence of bile salt and lecithin significantly contributed to the improved drug absorption. Together with the role of NaTC-HPMC complexes in assisting the drug solubilisation, our results also highlight the complex interplay between bile salts, excipients and drug absorption.