Prediction of the intestinal behavior of ester prodrugs: a comparison ofin vitro and in vivo models

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Gastrointestinal behavior of itraconazole in humans - Part 1: Supersaturation from a solid dispersion and a cyclodextrin-based solution

This study evaluated the fasted state gastrointestinal behavior of the lipophilic drug itraconazole, orally administered to healthy volunteers as either a solid dispersion (Sporanox® capsules) or a cyclodextrin-based solution (Sporanox® solution). Following intake of the drug products, gastric and duodenal fluids were aspirated and analyzed for itraconazole concentration, total content and solubilizing capacity. Release of itraconazole from the solid dispersion generated high and metastable supersaturated levels in the stomach, but the dissolved fraction in the duodenum remained extremely low (median 2.5%). After intake of the itraconazole solution, precipitation was limited in the stomach but pronounced in the small intestine. Still, the dissolved fraction of itraconazole in the duodenum (median 38%) appeared much higher than after intake of the solid dispersion, possibly explaining the improved absorption of itraconazole from the solution. As for the solid dispersion, the absorption-enabling ability of the solution appeared mainly related to increased intraluminal concentrations by means of supersaturation. Cyclodextrin-based solubilization of itraconazole occurred only in the case of limited intraluminal dilution, but did not further enhance itraconazole absorption. The obtained data will help to understand critical aspects of supersaturating drug delivery systems and act as direct reference for the optimization of in vitro simulation tools for gastrointestinal drug behavior.publisher: Elsevier articletitle: Gastrointestinal behavior of itraconazole in humans – Part 1: Supersaturation from a solid dispersion and a cyclodextrin-based solution journaltitle: International Journal of Pharmaceutics articlelink: http://dx.doi.org/10.1016/j.ijpharm.2017.04.029 associatedlink: http://dx.doi.org/10.1016/j.ijpharm.2017.04.057 content_type: article copyright: © 2017 Elsevier B.V. All rights reserved.status: publishe

The effect of food on the intraluminal behavior of abiraterone acetate in man

To relate the reported positive effect of food on the oral bioavailability of abiraterone to the intraluminal behavior of abiraterone acetate, an in vivo experiment was performed, in which duodenal fluids and plasma samples were collected from healthy volunteers after the administration of abiraterone acetate in fasted and postprandial conditions. The plasma concentration-time profiles confirmed the positive food effect. Nevertheless, intraduodenal concentrations of abiraterone acetate and abiraterone did not fully reflect this observation. This apparent discrepancy was explored by performing several in vitro experiments including solubility, dissolution, and transfer studies. Gastrointestinal transfer studies illustrated a positive impact of gastric processing of the abiraterone acetate formulation on the duodenal concentrations in the fasted state, which could not be observed in the postprandial condition. As the influence of gastric dissolution on the intraluminal concentrations in the small intestine declines aborally, it is most likely the superior solubility of abiraterone acetate and abiraterone in intestinal fluids of the fed state that dictates the food effect. Furthermore, N-oxide abiraterone sulfate and abiraterone sulfate appeared in the duodenum at significantly later time points than abiraterone, suggesting biliary excretion of these abiraterone metabolites; this was confirmed by in situ biliary excretion experiments in rats.publisher: Elsevier articletitle: The Effect of Food on the Intraluminal Behavior of Abiraterone Acetate in Man journaltitle: Journal of Pharmaceutical Sciences articlelink: http://dx.doi.org/10.1016/j.xphs.2016.03.008 content_type: article copyright: © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.status: publishe

Intestinal behavior of the ester prodrug tenofovir DF in humans

Tenofovir-disoproxil-fumarate (TDF) is a double ester prodrug which enables intestinal uptake of tenofovir (TFV) after oral administration in humans. In this study, prodrug stability was monitored in situ in the human intestine and in vitro using biorelevant media. In fasted state human intestinal fluids, the prodrug was completely degraded within 90min, resulting in the formation of the mono-ester intermediate and TFV; in fed state intestinal fluids, the degradation rate of TDF was slightly reduced and no TFV was formed. Intestinal fluid samples aspirated after administration of TDF confirmed extensive intraluminal degradation of TDF in fasted state conditions; a relatively fast absorption of TDF partly compensated for the degradation. Although food intake reduced intestinal degradation, the systemic exposure was not proportionally increased. The lower degradation in fed state conditions may be attributed to competing esterase substrates present in food, lower chemical degradation in the slightly more acidic environment and micellar entrapment, delaying exposure to the "degrading" intestinal environment. The results of this study demonstrate premature intestinal degradation of TDF and suggest that TFV may benefit from a more stable prodrug approach; however, fast absorption may compensate for fast degradation, indicating that prodrug selection should not be limited to stability assays.publisher: Elsevier articletitle: Intestinal behavior of the ester prodrug tenofovir DF in humans journaltitle: International Journal of Pharmaceutics articlelink: http://dx.doi.org/10.1016/j.ijpharm.2015.03.002 content_type: article copyright: Copyright © 2015 Elsevier B.V. All rights reserved.status: publishe

Rapid conversion of the ester prodrug abiraterone acetate results in intestinal supersaturation and enhanced absorption of abiraterone: In vitro, rat in situ and human in vivo studies

The aim of this study was to evaluate the intestinal disposition of abiraterone acetate, an ester prodrug of the anticancer agent abiraterone. Stability of the prodrug and solubility and dissolution characteristics of both abiraterone and abiraterone acetate were monitored in vitro. Moreover, the in vivo intraluminal concentrations of abiraterone and abiraterone acetate upon intake of one tablet of 250mg abiraterone acetate were assessed in healthy volunteers. The intestinal absorption resulting from the intraluminal behavior of the ester prodrug was determined using the rat in situ intestinal perfusion technique with mesenteric blood sampling. Simulated and aspirated human intestinal fluids of the fasted state were used as solvent systems. Upon incubation of abiraterone acetate in human intestinal fluids in vitro, rapid hydrolysis of the prodrug was observed, generating abiraterone concentrations largely exceeding the apparent solubility of abiraterone, suggesting the existence of intestinal supersaturation. These findings were confirmed in vivo, by intraluminal sampling of duodenal fluids upon oral intake of an abiraterone acetate tablet by healthy volunteers. Rat in situ intestinal perfusion experiments performed with suspensions of abiraterone and abiraterone acetate in human intestinal fluids of the fasted state revealed significantly higher flux values upon perfusion with the prodrug than with abiraterone. Moreover, rat in situ intestinal perfusion with abiraterone acetate suspensions in simulated fluids of the fasted state in presence or absence of esterases demonstrated that increased hydrolytic activity of the perfusion medium was beneficial to the intestinal absorption of abiraterone. In conclusion, the rapid hydrolysis of abiraterone acetate in the intraluminal environment appears to result in fast and extensive generation of abiraterone supersaturation, creating a strong driving force for abiraterone absorption.publisher: Elsevier articletitle: Rapid conversion of the ester prodrug abiraterone acetate results in intestinal supersaturation and enhanced absorption of abiraterone: In vitro, rat in situ and human in vivo studies journaltitle: European Journal of Pharmaceutics and Biopharmaceutics articlelink: http://dx.doi.org/10.1016/j.ejpb.2015.01.001 content_type: article copyright: Copyright © 2015 Elsevier B.V. All rights reserved.status: publishe

The association between health literacy and self-management abilities in adults aged 75 and older, and its moderators

Low health literacy is an important predictor of poor health outcomes and well-being among older adults. A reason may be that low health literacy decreases older adults' self-management abilities. We therefore assessed the association between health literacy and self-management abilities among adults aged 75 and older, and the impact of demographic factors, socioeconomic factors, and health status on this association. We used data of 1052 older adults, gathered for a previously conducted randomized controlled trial on Embrace, an integrated elderly care model. These data pertained to health literacy, self-management abilities, demographic background, socioeconomic situation, and health status. Health literacy was measured by the validated three-item Brief Health Literacy Screening instrument. Self-management abilities were measured by the validated Self-Management Ability Scale (SMAS-30). After adjustment for confounders, self-management abilities were poorer in older adults with low health literacy (beta = .34, p <.001). This was more pronounced in medium- to high-educated older adults than in low-educated older adults. Sex, age, living situation, income, presence of chronic illness, and mental health status did not moderate the association between health literacy and self-management abilities. Low health literacy is associated with poor self-management abilities in a wide range of older adults. Early recognition of low health literacy among adults of 75 years and older and interventions to improve health literacy might be very beneficial for older adults

Investigation of the intraluminal behavior of abiraterone acetate

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