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

Abstract

Aim: 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. Methods: 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. Results: 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 (11.4×10 -6 vs 7.4/8.0×10 -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. Conclusion: 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.

Evaluation of Ion-pair Formation of Adefovir to Improve Permeation across Artificial and Biological Membranes

“…where is the rate (µg/s) of total transport of the drug, A is the surface area (cm 2 ) and C0 is the initial donor concentration (µg/ml) (6). Possible cellular membrane damage was assessed by testing lactate dehydrogenase (LDH) release using an LDH kit (6) (LDH-P kit; Kimia Pajouhan; Iran).…”

“…Ester prodrugs are extremely prone to being hydrolyzed during oral absorption. Pre-systematic metabolism often leads to poor drug bioavailability (6). On the basis of the FDA guidelines for immediate-release solid oral dosage forms, ADV can be classified as a high solubility/low permeability drug (Class 3) (5).…”