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Postprandial Changes in Solubilizing Capacity of Human Intestinal Fluids for BCS Class II Drugs

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Abstract

Purpose

To explore the effect of the nutritional state on the solubilizing properties of human intestinal fluids (HIF) on a time-after-food administration basis.

Methods

HIF were collected in fractions of 30 min from five volunteers in the fasted, fed and fat-enriched fed state. In vitro solubility of five BCS class II drugs (danazol, diazepam, nifedipine, ketoconazole, indomethacin) was assessed in the intestinal fractions and simulated intestinal fluids.

Results

Solubilities in intestinal fractions were characterized by high time- and subject-dependent variability. For the non-ionized drugs, solubility in early intestinal fractions was higher in both fed states compared to the fasted state, and in the fat-enriched fed state compared to the fed state. Solubility in simulated intestinal fluids did not sufficiently predict the solubilizing capacity of the early postprandial phase. Solubility in HIF was shown to be determined by a complex interplay of various intraluminal parameters. For the ionized drugs, pH played a significant role for indomethacin (R 2 = 0.86); for the partly ionized ketoconazole other intraluminal parameters were also important.

Conclusions

Solubilizing capacity of HIF in the fed state is strongly time-dependent. Intraluminal dissolution may, therefore, vary with drug arrival time in the small intestine and constitute a source of variability in intestinal drug absorption.

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Abbreviations

BCS:

Biopharmaceutics Classification System

FaSSIF:

fasted state simulated intestinal fluid

FeSSIF:

fed state simulated intestinal fluid

FeSSIF v2:

fed state simulated intestinal fluid version 2

HIF:

human intestinal fluids

MLR:

multiple linear regression

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Acknowledgements

This research was funded by a Ph.D. grant of the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT-Vlaanderen), as well as from grants from the ‘Fonds voor Wetenschappelijk Onderzoek’ (FWO), Flanders and from the ‘Onderzoeksfonds’ of the K.U.Leuven, Belgium. We also wish to thank Rita Vos and Toon De Greef (Gastroenterology, University Hospitals Leuven, Belgium) for their assistance during the in vivo studies. Dr. Eric Deconinck is acknowledged for his expertise and assistance in performing the statistical analyses. D. Psachoulias was partly supported by the European Commission Program Socrates, Erasmus—Action 2.2.

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Authors and Affiliations

  1. Laboratory for Pharmacotechnology and Biopharmacy, Campus Gasthuisberg O&N 2, Box 921, Herestraat 49, 3000, Leuven, Belgium

    Sarah Clarysse, Joachim Brouwers, Pieter Annaert & Patrick Augustijns

  2. Laboratory for Biopharmaceutics and Pharmacokinetics, National and Kapodistrian University of Athens, Athens, Greece

    Dimitrios Psachoulias & Christos Reppas

  3. Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium

    Jan Tack

  4. Bioavailability and ADME Group, Unilever Research and Development, Vlaardingen, The Netherlands

    Guus Duchateau

Authors
  1. Sarah Clarysse
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  2. Dimitrios Psachoulias
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  3. Joachim Brouwers
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  4. Jan Tack
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  5. Pieter Annaert
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  7. Christos Reppas
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  8. Patrick Augustijns
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Correspondence to Patrick Augustijns.

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Clarysse, S., Psachoulias, D., Brouwers, J. et al. Postprandial Changes in Solubilizing Capacity of Human Intestinal Fluids for BCS Class II Drugs. Pharm Res 26, 1456–1466 (2009). https://doi.org/10.1007/s11095-009-9857-7

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  • DOI: https://doi.org/10.1007/s11095-009-9857-7

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