Vitamin E-TPGS increases absorption flux of an HIV protease inhibitor by enhancing its solubility and permeability.
OBJECTIVE
To investigate the effect of vitamin E-TPGS, d-alpha-tocopheryl polyethylene glycol 1000 succinate, on the solubility and permeability of amprenavir, a potent HIV protease inhibitor.


METHODS
The aqueous solubility of amprenavir was measured as a function of vitamin E-TPGS concentration. Directional transport through Caco-2 cell monolayers was determined in the presence and absence of vitamin E-TPGS and P-glycoprotein inhibitors. Absorption flux was estimated from Caco-2 cell permeability and aqueous solubility.


RESULTS
The solubility of amprenavir in a pH 7 buffer at 37 degrees C was 0.036+/-0.007 mg/mL. The solubility linearly increased with increasing vitamin E-TPGS concentration (above 0.2 mg/mL). Polarized transport was demonstrated in the basolateral to apical direction, exceeding apical to basolateral transport by a factor of 6. The active efflux system was inhibited by vitamin E-TPGS and known P-glycoprotein inhibitors verapamil and GF120918.


CONCLUSIONS
The solubility of amprenavir was improved in the presence of vitamin E-TPGS through micelle solubilization. Vitamin E-TPGS inhibits the efflux system and enhances the permeability of amprenavir. Overall, vitamin E-TPGS enhanced the absorption flux of amprenavir by increasing its solubility and permeability. The enhancement is essential to the development of the novel soft gelatin capsule formulation of amprenavir for use in the clinic.
Yu
L
L
Glaxo Wellcome, Inc., Research Triangle Park, North Carolina 27709, USA. yul@eder.fda.gov
Bridgers
A
A
Polli
J
J
Vickers
A
A
Long
S
S
Roy
A
A
Winnike
R
R
Coffin
M
M
D000465:Algorithms; D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002219:Carbamates; D002463:Cell Membrane Permeability / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005663:Furans; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D010539:Permeability / Q000187:drug effects; D011092:Polyethylene Glycols; D012995:Solubility; D013268:Stimulation, Chemical; D013449:Sulfonamides / Q000737:chemistry / Q000493:pharmacokinetics*; D014700:Verapamil / Q000494:pharmacology; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D002121:Calcium Channel Blockers; D002219:Carbamates; D005663:Furans; D017320:HIV Protease Inhibitors; D013449:Sulfonamides; D014810:Vitamin E; D011092:Polyethylene Glycols; C095108:amprenavir; D014700:Verapamil; C014225:tocophersolan