Fasted and fed state human duodenal fluids: Characterization, drug solubility, and comparison to simulated fluids and with human bioavailability
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Accurate in vivo predictions of intestinal absorption of low solubility drugs require knowing their solubility in physiologically relevant dissolution media. Aspirated human intestinal fluids (HIF) are the gold standard, followed by simulated intestinal HIF in the fasted and fed state (FaSSIF/FeSSIF). However, current HIF characterization data vary, and there is also some controversy regarding the accuracy of FaSSIF and FeSSIF for predicting drug solubility in HIF. This study aimed at characterizing fasted and fed state duodenal HIF from 16 human volunteers with respect to pH, buffer capacity, osmolarity, surface tension, as well as protein, phospholipid, and bile salt content. The fasted and fed state HIF samples were further used to investigate the equilibrium solubility of 17 representative low-solubility small-molecule drugs, six of which were confidential industry compounds and 11 were known and characterized regarding chemical diversity. These solubility values were then compared to reported solubility values in fasted and fed state HIF, FaSSIF and FeSSIF, as well as with their human bioavailability for both states. The HIF compositions corresponded well to previously reported values and current FaSSIF and FeSSIF compositions. The drug solubility values in HIF (both fasted and fed states) were also well in line with reported solubility data for HIF, as well as simulated FaSSIF and FeSSIF. This indicates that the in vivo conditions in the proximal small intestine are well represented by simulated intestinal fluids in both composition and drug equilibrium solubility. However, increased drug solubility in the fed vs. fasted states in HIF did not correlate with the human bioavailability changes of the same drugs following oral administration in either state.
Originalsprog | Engelsk |
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Tidsskrift | European Journal of Pharmaceutics and Biopharmaceutics |
Vol/bind | 163 |
Sider (fra-til) | 240-251 |
ISSN | 0939-6411 |
DOI | |
Status | Udgivet - 2021 |
Bibliografisk note
Funding Information:
This oral biopharmaceutics tools (Orbito) project received support from the Innovative Medicines Initiative Joint Undertaking (http://www.imi.europa.eu) under grant agreement number 115369, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-013) and EFPIA companies.
Funding Information:
This oral biopharmaceutics tools (Orbito) project received support from the Innovative Medicines Initiative Joint Undertaking (http://www.imi.europa.eu) under grant agreement number 115369, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-013) and EFPIA companies.
Publisher Copyright:
© 2021 The Author(s)
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