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Absorption enhancement of adefovir dipivoxil by incorporating MCT and ethyl oleate complex oil phase in emulsion.

Acta pharmacologica Sinica (2010-06-22)
Ping Li, Hong-zhen Yu, Xin-xin Zhang, Li Gan, Chun-liu Zhu, Yong Gan
ABSTRACT

To improve the oral absorption of adefovir dipivoxil (ADV) by employing MCT and the esterase inhibitor ethyl oleate (EO) as a complex oil phase in emulsion. EO was used as the esterase inhibitor, and its inhibitory effect on esterase activity was assessed in rat intestinal homogenates. ADV emulsions with or without EO were prepared. The emulsions' protective effect against intestinal metabolism was evaluated in rat luminal contents, ex vivo, as well as in vivo. The IC(50) of EO in intestinal mucosal homogenates was 2.2 mg/mL. The emulsions exhibited significant protective effects in rat luminal contents compared to a simple suspension (98.7%, 96.3%, 95.7% vs 74.7%, P<0.01). The permeability calculated from the emulsion containing EO was significantly different (11.4 x 10(-6) vs 7.4/8.0 x 10(-6), P<0.05) from the simple suspension or the emulsion without EO in an ex vivo assay. A bioavailability study in vivo revealed that emulsions containing both EO and MCT as a complex oil phase demonstrated 1.6- and 1.5-fold enhancements in area under the curve (AUC(0-12)) values (5358 vs 3386/3618, P<0.05), respectively, when compared with emulsions containing EO or MCT as a single oil phase. Heterotic lipid formulations (emulsions) with an esterase inhibitor (ie, EO) may be useful in protecting ester prodrugs from intestinal metabolism and increasing their oral bioavailability.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Ethyl oleate, 98%
Sigma-Aldrich
Ethyl oleate, tested according to Ph. Eur.
Sigma-Aldrich
Ethyl oleate, natural, ≥85%
Sigma-Aldrich
Ethyl oleate, technical grade, 70%