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


CONCLUSIONS
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.
Li
Ping
P
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China.
Yu
Hong-zhen
HZ
Zhang
Xin-xin
XX
Gan
Li
L
Zhu
Chun-liu
CL
Gan
Yong
Y
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D004655:Emulsions; D004791:Enzyme Inhibitors / Q000737:chemistry; D004950:Esterases / Q000037:antagonists & inhibitors; D020128:Inhibitory Concentration 50; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D009829:Oleic Acids / Q000737:chemistry*; D063065:Organophosphonates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000737:chemistry*
D000998:Antiviral Agents; D004655:Emulsions; D004791:Enzyme Inhibitors; D009829:Oleic Acids; D063065:Organophosphonates; D014280:Triglycerides; D004950:Esterases; D000225:Adenine; C106812:adefovir dipivoxil; C033180:ethyl oleate