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Improved understanding of the effect of food on drug absorption and bioavailability for lipophilic compounds using an intestinal pig perfusion model
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
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2008 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, Vol. 34, no 1, 22-29 p.Article in journal (Refereed) Published
Abstract [en]

The purpose of this study was to investigate the relative importance of mechanisms behind the effect of food on the intestinal absorption and bioavailability for low solubility compounds by applying a porcine single-pass perfusion model. Nanoparticle suspensions of the model compounds, danazol and cyclosporine were perfused through the jejunum in isotonic fluid alone (control) and isotonic fluid with a P-glycoprotein (P-gp) inhibitor (verapamil) or dietary and endogenous lipids added. The drugs were also administered as saturated solutions in the isotonic fluid containing lipids. Administration of cyclosporine together with verapamil increased the absorption compared to the control (1.6 times) suggesting an effect on jejunal permeability. However, addition of dietary lipids to the media led to a 50% reduction in the absorption of cyclosporine indicating lack of major effects by P-gp inhibition by lipids in vivo. The absorption of danazol was increased (2.6 times) when administered as a nanosuspension in lipid containing media compared to the control, but decreased (60%) when administered as a solution in the same media. This shows how important dissolution of the drug nanoparticles is in drug absorption. The difference in the effect of lipids in the absorption of cyclosporine and danazol when administered as nanosuspensions may be due to different distribution to the colloidal structures present in the media, thereby rendering the drugs' different diffusion rates in the perfused segment. In conclusion, solubilisation seems to be a more important factor than P-gp inhibition as an explanation for the food-drug interaction observed for several low solubility drugs. In addition, the partition into different colloidal structures seems to play a major role in the dissolution and absorption of poorly soluble drugs.

Place, publisher, year, edition, pages
2008. Vol. 34, no 1, 22-29 p.
Keyword [en]
intestinal absorption, permeability, biopharmaceutical classification system, bioavailability, food-drug interaction effects, low soluble drugs, P-glycoprotein, nanoparticles, verapamil, cyclosporine, danazol
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-94997DOI: 10.1016/j.ejps.2008.02.002ISI: 000256140400003PubMedID: 18387789OAI: oai:DiVA.org:uu-94997DiVA: diva2:169041
Available from: 2006-10-19 Created: 2006-10-19 Last updated: 2009-11-04Bibliographically approved
In thesis
1. Drug Dissolution under Physiologically Relevant Conditions In Vitro and In Vivo
Open this publication in new window or tab >>Drug Dissolution under Physiologically Relevant Conditions In Vitro and In Vivo
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The general aim of the present project was to increase the understanding of the in vivo dissolution of poorly soluble drugs and thereby improve possibility to predict in vivo solubility from substance properties. Increased understanding of the in vivo limitations of drug solubility could potentially also generate ideas for improved formulation principles for poorly soluble compounds and more relevant in vitro dissolution test methods used in formulation development.

The dynamic gastrointestinal secretory and enzymatic responses to a liquid meal were studied in human intestinal fluid (HIF) by in vivo perfusion of a nutritional drink. The main diversity found compared to simulated intestinal fluids was the presence of dietary lipids in fed human intestinal fluid. This difference was showed to be of importance in the solubility of low soluble drugs, since this parameter was underestimated in the simulated fluid. Thus suggesting that simulated intestinal fluids should be prepared with the addition of dietary lipids for better in vitro in vivo predictions.

Solubility and dissolution determinations in fasted and fed HIF showed that the solubility was higher in fed state fluid, probably owing to the higher concentration of lipids in this media. The higher solubility was correlated to both the lipophilicity and aqueous solubility of the drug. The dissolution rate also increased, but not to the same extent as the solubility. These findings need to be considered in the design of in vitro models and in the prediction of food effects on oral bioavailability of poorly soluble drugs.

In addition, an in vivo porcine perfusion study was performed to investigate importance of different mechanisms in food-drug interactions. The results showed that solubilisation might be a more important factor than P-gp inhibition for food-related effects on the intestinal absorption kinetics of Class II drugs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 65 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 39
Biopharmacy, solubility, drug dissolution, food effects, poorly soluble drugs, P-gp inhibition, drug absorption, pemeability, bile acids, phospholipids, human intestinal fluid, simulated intestinal fluid, neutral lipids, solid phase extraction, HPLC, Efflux, Biofarmaci
urn:nbn:se:uu:diva-7195 (URN)91-554-6684-2 (ISBN)
Public defence
2006-11-10, B41, Uppsala Biomedicinska Centrum, Husargatan 3, Uppsala, 10:15
Available from: 2006-10-19 Created: 2006-10-19Bibliographically approved

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