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Solubility Profiling of HIV Protease Inhibitors in Human Intestinal Fluids

Journal of Pharmaceutical Sciences, ISSN: 0022-3549, Vol: 102, Issue: 10, Page: 3800-3807
2013
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Article Description

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 CV fed = 60.6%, CV fasted = 40.4%) was higher as compared with the intrasubject variability ( CV fed = 41.3%, CV fasted = 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. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3800–3807, 2013

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