Fasted and fed state human duodenal fluids: Characterization, drug solubility, and comparison to simulated fluids and with human bioavailability
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Fasted and fed state human duodenal fluids : Characterization, drug solubility, and comparison to simulated fluids and with human bioavailability. / Dahlgren, D.; Venczel, M.; Ridoux, J. P.; Skjöld, C.; Müllertz, A.; Holm, R.; Augustijns, P.; Hellström, P. M.; Lennernäs, H.
I: European Journal of Pharmaceutics and Biopharmaceutics, Bind 163, 2021, s. 240-251.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Fasted and fed state human duodenal fluids
T2 - Characterization, drug solubility, and comparison to simulated fluids and with human bioavailability
AU - Dahlgren, D.
AU - Venczel, M.
AU - Ridoux, J. P.
AU - Skjöld, C.
AU - Müllertz, A.
AU - Holm, R.
AU - Augustijns, P.
AU - Hellström, P. M.
AU - Lennernäs, H.
N1 - Publisher Copyright: © 2021 The Author(s)
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - Bioavailability
KW - Drug absorption
KW - Drug delivery
KW - Drug dissolution
KW - Drug solubility
KW - Food effects
KW - Human intestinal fluids
U2 - 10.1016/j.ejpb.2021.04.005
DO - 10.1016/j.ejpb.2021.04.005
M3 - Journal article
C2 - 33872761
AN - SCOPUS:85104670017
VL - 163
SP - 240
EP - 251
JO - European Journal of Pharmaceutics and Biopharmaceutics
JF - European Journal of Pharmaceutics and Biopharmaceutics
SN - 0939-6411
ER -
ID: 279127297