The Physicochemical Properties, in Vitro Metabolism and Pharmacokinetics of a Novel Ester Prodrug of EXP3174

Title
The Physicochemical Properties, in Vitro Metabolism and Pharmacokinetics of a Novel Ester Prodrug of EXP3174
Author(s)
용철순엄의동[엄의동]김한경[김한경]이원석[이원석]이관선[이관선]우종수[우종수]최한곤[최한곤]서기현[서기현]
Keywords
II RECEPTOR ANTAGONIST; LOSARTAN; HYPERTENSION; ABSORPTION; EFFICACY; ANIMALS; HUMANS; RATS
Issue Date
201009
Publisher
AMER CHEMICAL SOC
Citation
MOLECULAR PHARMACEUTICS, v.7, no.6, pp.2132 - 2140
Abstract
EXP3174 is the major active metabolite of losartan, a drug currently widely used for the treatment of cardiovascular diseases. This study was designed to evaluate the physicochemical properties of EXP3174-pivoxil (a novel synthesized prodrug of EXP3174) and characterize its metabolism, regional intestinal absorption and pharmacokinetics by in vitro and in vivo studies. An in vitro metabolism study was conducted in liver and intestinal S9 fractions from different species including rat, dog and human. In vivo absorption was investigated following regional intestinal dosing in rats, and the pharmacokinetics was determined using rats after a single oral administration. EXP3174-pivoxil exhibited predictable stability in the aqueous solution within a pH range of 1.2-9.0 as well as in the solid form of powder. An in vitro metabolism study revealed that EXP3174-pivoxil was rapidly and efficiently converted into EXP3174 by enzymatic hydrolysis. The dose administered into the duodenum and jejunum resulted in higher values for the AUC(0-24h) and C-max than those following ileum dosing (p < 0.05). Furthermore, the AUC(0-24h) and values for EXP3174 increased in a dose-dependent manner as dose increased from 0.5 to 5 mg/kg. A comparable AUC(0-24h), shortened T-max and a significant increase in the plasma C-max of EXP3174 were observed following oral administration of EXP3174-pivoxil (as EXP3174, 1 mg/kg) compared with those of losartan (as EXP3174, 5 mg/kg) in rats, suggesting faster absorption and a 5-fold enhancement in the bioavailability of EXP3174. These results suggest that EXP3174-pivoxil may serve as a more effective drug even at lower clinical doses by exhibiting increased bioavailability and faster therapeutic response, compared with losartan.
URI
http://hdl.handle.net/YU.REPOSITORY/23692http://dx.doi.org/10.1021/mp100166c
ISSN
1543-8384
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약학대학 > 약학부 > Articles
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