PMID- 29902511
OWN - NLM
STAT- MEDLINE
DCOM- 20190828
LR  - 20190828
IS  - 1879-0720 (Electronic)
IS  - 0928-0987 (Linking)
VI  - 121
DP  - 2018 Aug 30
TI  - Human intestinal fluid factors affecting intestinal drug permeation in vitro.
PG  - 338-346
LID - S0928-0987(18)30263-X [pii]
LID - 10.1016/j.ejps.2018.06.007 [doi]
AB  - Intestinal permeability assessment is an important aspect of drug development, 
      which strongly depends on the solvent system used in the intestinal donor 
      compartment. For this purpose, human intestinal fluids (HIF) can be considered as 
      the golden standard. A recent study demonstrated a reduced apparent permeation 
      across rat intestinal tissue from fed versus fasted state HIF for 9 out of 16 
      compounds tested. Commercially available fed and fasted state simulated fluids 
      (FeSSIF and FaSSIF) reproduced this food effect for only 3 out of 16 compounds. 
      To elucidate this observed difference, the current study assessed the impact of 
      relevant intestinal fluid factors (bile salt, phospholipids, cholesterol, free 
      fatty acids (FFA), monoacylglycerides (MAG)) and 2-factor interactions at a fixed 
      pH of 6.5 on drug permeation across both rat tissue (Ussing chambers setup) and 
      an artificial membrane (dialysis setup). Four representative compounds were 
      selected for the permeation experiments: for propranolol and indomethacin, a 
      food-induced permeation reduction was previously seen in both HIF and SIF; for 
      metoprolol and darunavir, a reduction was only seen in HIF. Using a fractional 
      2(5-1) design of experiments (DoE) approach, 16 SIF combinations were defined as 
      donor media for permeation studies. In the Ussing chambers (rat tissue), FFA and 
      MAG reduced the permeation for all 4 compounds. Only for propranolol and 
      indomethacin, permeation was further reduced by bile salts and phospholipids. 
      This explains why the use of FeSSIF vs FaSSIF, lacking FFA and MAG, predicted a 
      negative food effect for propranolol and indomethacin but not for metoprolol and 
      darunavir. In the dialysis set-up using an artificial membrane, significantly 
      higher permeation rates compared to the Ussing chambers were observed. Under 
      those conditions, FFA and MAG no longer reduced permeation, while bile salts and 
      phospholipids still did. This may indicate that lipidic structures can provide 
      depot release in the case of a dynamic equilibrium between free and entrapped 
      drug.
CI  - Copyright (c) 2018 Elsevier B.V. All rights reserved.
FAU - Riethorst, Danny
AU  - Riethorst D
AD  - KU Leuven, Drug Delivery and Disposition, Department of Pharmaceutical and 
      Pharmacological Sciences, Leuven, Belgium.
FAU - Brouwers, Joachim
AU  - Brouwers J
AD  - KU Leuven, Drug Delivery and Disposition, Department of Pharmaceutical and 
      Pharmacological Sciences, Leuven, Belgium.
FAU - Motmans, Jens
AU  - Motmans J
AD  - KU Leuven, Drug Delivery and Disposition, Department of Pharmaceutical and 
      Pharmacological Sciences, Leuven, Belgium.
FAU - Augustijns, Patrick
AU  - Augustijns P
AD  - KU Leuven, Drug Delivery and Disposition, Department of Pharmaceutical and 
      Pharmacological Sciences, Leuven, Belgium. Electronic address: 
      patrick.augustijns@kuleuven.be.
LA  - eng
PT  - Journal Article
DEP - 20180615
PL  - Netherlands
TA  - Eur J Pharm Sci
JT  - European journal of pharmaceutical sciences : official journal of the European 
      Federation for Pharmaceutical Sciences
JID - 9317982
RN  - 0 (Bile Acids and Salts)
RN  - 0 (Fatty Acids)
RN  - 0 (Membranes, Artificial)
RN  - 0 (Pharmaceutical Preparations)
RN  - 0 (Phospholipids)
RN  - 97C5T2UQ7J (Cholesterol)
SB  - IM
MH  - Animals
MH  - Bile Acids and Salts/metabolism
MH  - Cholesterol/metabolism
MH  - Fatty Acids/metabolism
MH  - Humans
MH  - *Intestinal Absorption
MH  - Intestinal Mucosa/*metabolism
MH  - Intestinal Secretions/*metabolism
MH  - Male
MH  - Membranes, Artificial
MH  - Permeability
MH  - Pharmaceutical Preparations/metabolism
MH  - Phospholipids/metabolism
MH  - Rats, Wistar
OTO - NOTNLM
OT  - Design of experiments
OT  - Human intestinal fluids
OT  - Intestinal absorption
OT  - Permeation
OT  - Solvent systems
EDAT- 2018/06/15 06:00
MHDA- 2019/08/29 06:00
CRDT- 2018/06/15 06:00
PHST- 2018/02/16 00:00 [received]
PHST- 2018/05/16 00:00 [revised]
PHST- 2018/06/10 00:00 [accepted]
PHST- 2018/06/15 06:00 [pubmed]
PHST- 2019/08/29 06:00 [medline]
PHST- 2018/06/15 06:00 [entrez]
AID - S0928-0987(18)30263-X [pii]
AID - 10.1016/j.ejps.2018.06.007 [doi]
PST - ppublish
SO  - Eur J Pharm Sci. 2018 Aug 30;121:338-346. doi: 10.1016/j.ejps.2018.06.007. Epub 
      2018 Jun 15.