Mohammed I. El-Gamal, Hanan S. Anbar and Chang-Hyun Oh
Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates
In this work, a series of six new ester prodrugs of olmesartan was synthesized. Their in vitro stabilities in simulated gastric juice, rat plasma, and rat liver microsomes were tested. And the pharmacokinetic parameters for olmesartan after oral administration of the prodrugs into rats were also estimated and compared with those in case of olmesartan medoxomil. Two compounds demonstrated high stability in simulated gastric juice and were rapidly metabolized to olmesartan in rat liver microsomes and rat plasma in vitro. This means that they will be stable in stomach before absorption, then will be rapidly metabolized to the parent drug after oral absorption. In animal studies, Cmax and AUClast parameters were significantly increased in case of these two prodrugs, compared with olmesartan medoxomil. The peak plasma concentrations of olmesartan (Cmax) were significantly higher (290% and 52% increase) for the two prodrugs than those observed after administration of olmesartan medoxomil. The AUClast values of olmesartan were also significantly greater (157% and 46% higher) in case of the two new prodrugs than that of olmesartan medoxomil. These results indicate that these two compounds are promising prodrugs of olmesartan with markedly increased oral bioavailability.