The effect of different lipid based formulations on the oral absorption of lipophilic drugs: The ability of in vitro lipolysis and consecutive ex vivo intestinal permeability data to predict in vivo bioavailability in rats

Arik Dahan, Amnon Hoffman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

202 Scopus citations

Abstract

The purpose of this study was to investigate the impact of different lipid based formulations of lipophilic drugs on in vitro solubilization and intestinal ex vivo permeability processes. Thereafter, to evaluate the ability of these in vitro and ex vivo results to predict the corresponding in vivo oral bioavailability data. The dissolution of dexamethasone and griseofulvin in long (LCT), medium (MCT) and short (SCT) chain triglyceride formulations was tested in a dynamic in vitro lipolysis model. Following the completion of the lipolysis, the permeability through the gut wall was tested in an ex vivo side-by-side diffusion chamber model. The absolute oral bioavailability of the drugs from the tested formulations was investigated in rats. The dynamic in vitro lipolysis experiments indicated an equivalent performance of the different formulations for dexamethasone, and a performance rank order of MCT > LCT > SCT > H2O for griseofulvin. In the subsequent ex vivo permeability studies, the SCT formulation caused enhanced permeation with doubled permeability coefficient for both drugs. The in vivo bioavailability of both drugs correlated well with the in vitro data, i.e., LCT = MCT = SCT for dexamethasone and MCT > LCT > SCT > H2O for griseofulvin, despite the significant augmented intestinal permeability produced by the SCT formulation. In conclusion, the in vitro lipolysis model was found to be useful in the intelligent optimization of oral lipid formulations for lipophilic drugs, even in the case where the intestinal permeability is enhanced by the formulation. The SCT vehicle showed to be a potential permeability enhancer; however, for class 2 compounds, the permeability does not correlate with in vivo bioavailability.

Original languageAmerican English
Pages (from-to)96-105
Number of pages10
JournalEuropean Journal of Pharmaceutics and Biopharmaceutics
Volume67
Issue number1
DOIs
StatePublished - Aug 2007

Bibliographical note

Funding Information:
This work is a part of Arik Dahan PhD dissertation. This study was supported by the Israeli Consortium of Pharmalogica. The authors thank Inbal Yifrach for excellent technical assistance, and Dr. Josh Backon for constructive comments. A. Hoffman is affiliated with David R. Bloom Center of Pharmacy.

Keywords

  • Bioavailability
  • Ex vivo Ussing chamber
  • In vitro lipolysis
  • Intestinal absorption
  • Intestinal permeability
  • Lipid based formulations
  • Lipophilic drugs

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