Solubility profiling of HIV protease inhibitors in human intestinal fluids.
The present study pursued to profile the intestinal solubility of nine HIV protease inhibitors (PIs) in fasted- and fed-state human intestinal fluids (FaHIF, FeHIF) aspirated from four volunteers. In addition, the ability of fasted- and fed-state simulated intestinal fluids (FaSSIF, FeSSIF) to predict the intestinal solubility was evaluated. All PIs were poorly soluble in FaHIF (from 7 μM for ritonavir to 327 μM for darunavir) and FeHIF (from 15 μM for atazanavir to 409μM for darunavir). For four of nine PIs, food intake significantly enhanced the solubilizing capacity of intestinal fluids (up to 18.4-fold increase for ritonavir). The intersubject variability (average coefficient of variance CVfed = 60.6%, CVfasted = 40.4%) was higher as compared with the intrasubject variability (CVfed = 41.3%, CVfasted = 20.5%). PI solubilities correlated reasonably well between FaSSIF and FaHIF (R = 0.817), but not between FeSSIF and FeHIF (R = 0.617). To conclude, postprandial conditions increased the inter- and intrasubject variability of the PIs. The inability of FeSSIF to accurately predict the FeHIF solubility emphasizes the need for a multivariate approach to determine solubility profiles, taking into account solid-state characteristics, pH, mixed bile acid/phospholipid micelles, and digestive products.
Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium.
Benjamin
B
Wuyts
Joachim
J
Brouwers
Raf
R
Mols
Jan
J
Tack
Pieter
P
Annaert
Patrick
P
Augustijns
D000328:Adult; D001647:Bile Acids and Salts / Q000378:metabolism; D001826:Body Fluids / Q000378:metabolism*; D004435:Eating; D005215:Fasting / Q000378:metabolism; D005260:Female; D018565:Food-Drug Interactions; D005766:Gastrointestinal Contents; D017320:HIV Protease Inhibitors / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D008823:Micelles; D019518:Postprandial Period; D019438:Ritonavir / Q000378:metabolism; D012995:Solubility; D055815:Young Adult
D001647:Bile Acids and Salts; D017320:HIV Protease Inhibitors; D008823:Micelles; D019438:Ritonavir
FaSSIF; FeSSIF; HIV protease inhibitors; food interactions; human intestinal fluids; in vitro models; intestinal absorption; poorly water-soluble drugs; solubility