The influence of donor and reservoir additives on Caco-2 permeability and secretory transport of HIV protease inhibitors and other lipophilic compounds.
OBJECTIVE
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 Papp 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.
Aungst
B J
BJ
The DuPont Pharmaceuticals Company, Wilmington, Delaware 19880-0400, USA. bruce.j.aungst@dupontpharma.com
Nguyen
N H
NH
Bulgarelli
J P
JP
Oates-Lenz
K
K
D000081:Acetamides / Q000494:pharmacology*; D000418:Albumins / Q000494:pharmacology*; D001381:Azepines / Q000493:pharmacokinetics; D018938:Caco-2 Cells / Q000187:drug effects* / Q000378:metabolism*; D002219:Carbamates; D002463:Cell Membrane Permeability / Q000187:drug effects; D005663:Furans; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics*; D006801:Humans; D019469:Indinavir / Q000493:pharmacokinetics; D007408:Intestinal Absorption / Q000187:drug effects; D019888:Nelfinavir / Q000493:pharmacokinetics; D019438:Ritonavir / Q000493:pharmacokinetics; D012997:Solvents; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000493:pharmacokinetics; D014508:Urea / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D000081:Acetamides; D000418:Albumins; D001381:Azepines; D002219:Carbamates; C116353:DMP 850; C116354:DMP 851; D005663:Furans; D017320:HIV Protease Inhibitors; D012997:Solvents; D013449:Sulfonamides; C095108:amprenavir; D019469:Indinavir; D014508:Urea; D019888:Nelfinavir; C013959:dimethylacetamide; D019438:Ritonavir; C099851:DMP 450