TY - JOUR
T1 - Developing a predictive in vitro dissolution model based on gastrointestinal fluid characterisation in rats
AU - Christfort, Juliane Fjelrad
AU - Strindberg, Sophie
AU - Plum, Jakob
AU - Hall-Andersen, Jonatan
AU - Janfelt, Christian
AU - Nielsen, Line Hagner
AU - Müllertz, Anette
PY - 2019
Y1 - 2019
N2 - The influence of physiological factors on the solubility of drug compounds has been thoroughly investigated in humans. However, as these factors vary between species and since many in vivo studies are carried out in rats or mice, it has been difficult to establish sufficient in vitro in vivo relations. The aim of this study was to develop a physiologically relevant in vitro dissolution model simulating the gastrointestinal (GI) fluids of fasted rats and compare it to previously published in vitro and in vivo data. To develop the in vitro model, the pH was measured in situ in six segments of the GI tract of anesthetised rats, then the fluids from the stomach, the proximal and the distal small intestine were collected and characterized with regard to osmolality, and bile acid and phospholipid concentration. The pH and osmolality were found to increase throughout the GI tract. The bile acids and phospholipids were present in high concentrations in the proximal small intestine, and the bile acid concentration doubled in the distal part, where the phospholipid concentration decreased. Matrix-assisted laser desorption ionisation mass spectrometry imaging was applied on a cross section of the small intestine, to study which bile acids and phospholipid classes were present in the small intestine of rats. Both cholic acid, taurocholic acid and glycocholic acid were detected, and phosphatidylcholine (34:2) was found to be mainly present in the intestinal wall or mucus, whereas lysophosphatidylcholine (16:0) was also detected in the lumen. Based on these observations, biorelevant media were developed to simulate fluids in the stomach and the proximal part of the small intestine in fasted rats. The media were implemented in a two-step in vitro dissolution model, which was found to better predict the in vivo performance of furosemide, when compared to previously published in vitro and in vivo data.
AB - The influence of physiological factors on the solubility of drug compounds has been thoroughly investigated in humans. However, as these factors vary between species and since many in vivo studies are carried out in rats or mice, it has been difficult to establish sufficient in vitro in vivo relations. The aim of this study was to develop a physiologically relevant in vitro dissolution model simulating the gastrointestinal (GI) fluids of fasted rats and compare it to previously published in vitro and in vivo data. To develop the in vitro model, the pH was measured in situ in six segments of the GI tract of anesthetised rats, then the fluids from the stomach, the proximal and the distal small intestine were collected and characterized with regard to osmolality, and bile acid and phospholipid concentration. The pH and osmolality were found to increase throughout the GI tract. The bile acids and phospholipids were present in high concentrations in the proximal small intestine, and the bile acid concentration doubled in the distal part, where the phospholipid concentration decreased. Matrix-assisted laser desorption ionisation mass spectrometry imaging was applied on a cross section of the small intestine, to study which bile acids and phospholipid classes were present in the small intestine of rats. Both cholic acid, taurocholic acid and glycocholic acid were detected, and phosphatidylcholine (34:2) was found to be mainly present in the intestinal wall or mucus, whereas lysophosphatidylcholine (16:0) was also detected in the lumen. Based on these observations, biorelevant media were developed to simulate fluids in the stomach and the proximal part of the small intestine in fasted rats. The media were implemented in a two-step in vitro dissolution model, which was found to better predict the in vivo performance of furosemide, when compared to previously published in vitro and in vivo data.
KW - Biorelevant media
KW - Gastrointestinal fluids
KW - In vitro in vivo correlation
KW - Rats
U2 - 10.1016/j.ejpb.2019.07.007
DO - 10.1016/j.ejpb.2019.07.007
M3 - Journal article
C2 - 31288077
AN - SCOPUS:85068511341
VL - 142
SP - 307
EP - 314
JO - European Journal of Pharmaceutics and Biopharmaceutics
JF - European Journal of Pharmaceutics and Biopharmaceutics
SN - 0939-6411
ER -