Postprandial changes in solubilizing capacity of human intestinal fluids for BCS class II drugs.
OBJECTIVE
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.
Clarysse
Sarah
S
Laboratory for Pharmacotechnology and Biopharmacy, Campus Gasthuisberg O&N 2, Herestraat 49, Leuven, Belgium.
Psachoulias
Dimitrios
D
Brouwers
Joachim
J
Tack
Jan
J
Annaert
Pieter
P
Duchateau
Guus
G
Reppas
Christos
C
Augustijns
Patrick
P
D004032:Diet; D004386:Duodenum / Q000502:physiology*; D005260:Female; D018565:Food-Drug Interactions; D005766:Gastrointestinal Contents / Q000737:chemistry*; D006801:Humans; D016014:Linear Models; D008297:Male; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000032:analysis* / Q000737:chemistry; D019518:Postprandial Period; D012995:Solubility; D013997:Time Factors
D004364:Pharmaceutical Preparations