ABSTRACT
Synthesis of a new ester prodrug of olmesartan, olmesartan hexetil (1), is described. It is in vitro stabilities and in vivo pharmacokinetics (PK) were evaluated. It showed high stability in simulated gastric juice, and was rapidly hydrolyzed to olmesartan in rat liver microsomes and rat plasma in vitro. C(max) and AUC(last) for olmesartan were significantly increased in case of hexetil prodrug, compared with olmesartan medoxomil. Olmesartan hexetil is proposed to be an efficient prodrug of olmesartan with markedly increased oral bioavailability.
Subject(s)
Antihypertensive Agents/pharmacokinetics , Imidazoles/chemical synthesis , Imidazoles/pharmacokinetics , Prodrugs/chemical synthesis , Prodrugs/pharmacokinetics , Tetrazoles/chemical synthesis , Tetrazoles/pharmacokinetics , Angiotensin II Type 1 Receptor Blockers/chemical synthesis , Angiotensin II Type 1 Receptor Blockers/pharmacokinetics , Animals , Biological Availability , Drug Discovery , Drug Stability , Esters/chemical synthesis , Gastric Juice/chemistry , Gastric Juice/metabolism , Imidazoles/blood , Male , Microsomes, Liver/metabolism , Rats , Rats, Sprague-Dawley , Tetrazoles/bloodABSTRACT
Synthesis of new ester prodrugs of olmesartan is described. Their in vitro stabilities in simulated gastric juice, rat plasma, and rat liver microsomes were tested. And the pharmacokinetic parameters for olmesartan after their oral administration were also estimated and compared with those in case of olmesartan medoxomil. Compounds 13 and 14 demonstrated high stability in simulated gastric juice and were rapidly metabolized to olmesartan in rat liver microsomes and rat plasma in vitro. In addition, C(max) and AUC(last) parameters were significantly increased in case of compounds 13 and 14 compared with olmesartan medoxomil. These results indicate that compounds 13 and 14 with cyclohexylcarboxyethyl and adamantylcarboxymethyl promoieties, respectively, are promising prodrugs of olmesartan with markedly increased oral bioavailability.