Intestinal absorption characteristics of the low solubility thiocarboxanilide UC-781.
The aim of this study was to determine the intestinal absorption characteristics of the antiviral agent UC-781 and to optimize the experimental conditions of the in vitro system for low solubility compounds. The absorption potential of UC-781 was studied with the Caco-2 system and with the rat intestinal perfusion technique. The low solubility of UC-781 required the use of solubility/dissolution rate enhancing agents (e.g. VitE-TPGS, Gelucire 44/14). The creation of sink conditions in the receiver compartment of the Caco-2 system was a prerequisite to reliably study the transport of this poorly soluble compound. After inclusion of VitE-TPGS in the acceptor solution, UC-781 could be characterized as a class II drug of the Biopharmaceutical Classification System (low solubility, high permeation across membranes). A significant concentration-dependent decrease in transport of UC-781 was observed upon increasing the concentration of VitE-TPGS in the apical compartment. This observation contrasts to the absorption enhancing properties of VitE-TPGS, and can probably be attributed to a decrease in the concentration of free UC-781 when using higher concentrations of the solubility/dissolution rate enhancing agents. The use of Gelucire 44/14 as a solubilizing agent resulted in a batch-dependent degradation of UC-781. The inclusion of the solubility/dissolution rate-enhancing agent VitE-TPGS did not result in absorption enhancement in the intestinal perfusion technique.
Deferme
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S
Laboratory of Pharmacotechnology and Biopharmacy, Katholieke Universiteit Leuven, O&N, Gasthuisberg, 3000 Leuven, Belgium.
Van Gelder
J
J
Ingels
F
F
Van den Mooter
G
G
De Buck
S
S
Balzarini
J
J
Naesens
L
L
De Clercq
E
E
Kinget
R
R
Augustijns
P
P
D000813:Anilides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D001692:Biological Transport; D018938:Caco-2 Cells; D002851:Chromatography, High Pressure Liquid; D016503:Drug Delivery Systems; D005663:Furans / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D017551:Microdialysis; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D013854:Thioamides
D000813:Anilides; D005663:Furans; D018894:Reverse Transcriptase Inhibitors; D013854:Thioamides; C100668:UC-781