NDLI: The Influence of Donor and Reservoir Additives on Caco-2 Permeability and Secretory Transport of HIV Protease Inhibitors and Other Lipophilic Compounds

Content Provider	Springer Nature Link
Author	Aungst, Bruce J Nguyen, Nhung H Bulgarelli, James P Oates Lenz, Kristi
Copyright Year	2000
Abstract	Purpose. To optimize the conditions for determining Caco-2 permeation of HIV protease inhibitors and other lipophilic compounds, and to compare cyclic urea HIV protease inhibitors with marketed compounds. Methods. Absorptive and secretory Caco-2 membrane permeation studies were performed with HIV protease inhibitors and various reference compounds, examining the effects of adding the solubilizing agents dimethylacetamide (DMAC) and albumin in donor and reservoir compartments, respectively. Results. DMAC was useful as an additive in the donor vehicles, increasing the dissolved concentrations of poorly water-soluble HIV protease inhibitors, and enabling more reliable determination of P$_{app}$ values. Donor vehicles containing up to 5% DMAC could be used without altering Caco-2 barrier function, as indicated by the lack of effect on permeabilities of reference compounds with diverse absorption characteristics. The utilization of a reservoir containing albumin resulted in marked increases in absorptive P$_{app}$ values for some HIV protease inhibitors as well as other lipophilic, highly protein bound compounds, consistent with albumin increasing the release of these compounds from the cell monolayer. Conclusions. Poorly soluble, lipophilic, highly bound compounds may require using solubilizing agents in the donor and reservoir compartments of Caco-2 permeation experiments for estimating in vivo absorption potential. If the reservoir does not provide adequate sink conditions, cellular retention could over-emphasize the contributions of secretory transport. The cyclic ureas, DMP 450, DMP 850, and DMP 851, have Caco-2 permeabilities suggestive of moderate-to-high oral absorption potential in humans.
Starting Page	1175
Ending Page	1180
Page Count	6
File Format	PDF
ISSN	07248741
Journal	Pharmaceutical Research
Volume Number	17
Issue Number	10
e-ISSN	1573904X
Language	English
Publisher	Kluwer Academic Publishers-Plenum Publishers
Publisher Date	2000-01-01
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Pharmacology/Toxicology Pharmacy Biochemistry Medical Law Biomedical Engineering
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Pharmacology Molecular Medicine Pharmacology (medical) Biotechnology Pharmaceutical Science

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