Olmesartan medoxomil

Recent studies with quinoline-4-carboxylic acid angiotensin II receptor antagonists have confirmed the interest of (oxodioxolyl)methyl esters as prodrugs with improved oral bioavailability and efficacy in laboratory animals [79], Olmesartan, another angiotensin II receptor antagonist, has also been derivatized to a (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl carboxylate designated as olmesartan medoxomil [80], In this case, both human serum albumin and arylesterase (presumably EC 3.1.1.2, although paraoxonase cannot be excluded) were shown to be involved in hydrolysis. 

USAN Olmesartan medoxomil Trade name Benicat ... 

Olmesartan medoxomil (5) is also a prodrug that is rapidly and completely bioactivated by ester hydrolysis to olmesartan (RNH-6270) during absorption from the gastrointestinal tract (Warner and Jarvis, 2002). Olmesartan is eliminated in a biphasic manner with an elimination half-life of 14 h. The absolute bioavailabihty of olmesartan is 26% and peak plasma concentration is reached in 1 -2 h. Following the rapid and complete conversion of 5 to olmesartan, there is virtually no further metabolism of olmesartan. Olmesartan is eliminated from the bile and kidneys in about a 60 40 ratio. 

The synthesis of olmesartan medoxomil (5) by the Sankyo Company is illustrated in Scheme 9.8. Heating of diaminomaleonitrile (34) with trimethylorthobutyrate provided imidazole-4,5-dicarbonitrile 35, which underwent hydrolysis to the dicarboxylic acid followed by esterification to give imidazole diester 36. Addition of methyl magnesium... 

Benicar HCT (olmesartan medoxomil) Angiotensin II receptor blocker a 0.1 0.4... 

Candesartan cilexetil (converted to candesartan), olmesartan medoxomil (converted to olmesartan) and losartan (converted to EXP-3174 which is 10- to 40-times more potent than losartan) are prodrugs. While losartan is a reversible, surmountable competitive inhibitor, EXP-3174 is a reversible noncompetitive inhibitor of the AT, receptor therefore, losartan may compete for the same receptor. All other ARBs are pharmacologically active substances. Losartan requires a 50% initial dose reduction in patients with impaired hepatic function [21]. All agents can be dosed once daily, and telmisartan has the longest plasma half-life. 

Olmesartan medoxomil is an angiotensin-II-receptor antagonist that blocks vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the ATj receptor in vascular smooth muscle. It is indicated in the treatment of hypertension. 

Olmesartan medoxomil (Benicar) is an inactive ester prodrug that is completely hydrolyzed to the active form, olmesartan, during absorption from the GI tract. Peak plasma levels are obtained 1.4 to 2.8 hours after oral administration, and the plasma half-life is between 10 and 15 hours. Plasma clearance of olmesartan is through both renal elimination and biliary excretion. Although renal impairment and hepatic disease decrease the plasma clearance of olmesartan, no dose adjustment is required in patients with mild to moderate renal or hepatic impairment. The oral dosage of olmesartan medoxomil is 20 to 40 mg, once daily. 

Fig. 28.17. Structures of losartan analogues. The highlighted portions of candesartan cilexitil and olmesartan medoxomil are hydrolyzed via esterases to produce their respective active, carboxylate metabolites.

Approximately 14% of a dose of losartan is oxidized by the isozymes CYP2C9 and CYP3A4 to produce EXP-3174, a noncompetitive ATi receptor antagonist that is 10- to 40-fold more potent than losartan (Fig. 28.19). The overall cardiovascular effects seen with losartan result from the combined actions of the parent drug and the active metabolite thus, losartan should not be considered to be a pro-drug (1). As previously mentioned, candesartan cilexetil and olmesartan medoxomil are rapidly and completely hydrolyzed to candesartah ahd olmesartah, respectively, in the intestinal wall. 

Olmetec (Olmesartan medoxomil). Daiichi Sankyo UK Ltd UK Summary of product characteristics, August 2006. 

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