Valsartan metabolism

Valsartan (2) is a nonheterocyclic antagonist in which the imidazole of losartan has been replaced with an acylated amino acid. It is a very potent ATj antagonist (IC50 =1.6 nM). There is only one metabolite, valeryl 4-hydroxy valsartan, and it is inactive. The enzymes responsible for valsartan metabolism have not been identihed, but do not seem to be P450 CYP isozymes. Food decreases the absorption by 40%. Valsartan (2) is excreted in the bile (70%) and by the kidneys (30%). [See Chiolero and Burnier (1998).]... 

ANGIOTENSIN II RECEPTOR ANTAGONISTS IMATINIB t plasma concentrations of losartan, irbesartan and valsartan Imatinib is a potent inhibitor of CYP2C9 isoenzymes, which metabolize these angiotensin II receptor blockers Monitor for toxic effects of losartan, e.g. hypotension, hyperkalaemia, diarrhoea, cough, vertigo and liver toxicity... 

Valsartan is a highly selective antagonist at angiotensin II type 1 (ATi) receptors (1). It has a half-life of about 8 hours, and is metabolized to a negligible extent. Most of its clearance is via the feces. 

Yamashiro, W., Maeda, K., Hirouchi, M., Adachi, Y., Hu, Z. and Sugiyama, Y. (2006) Involvement of transporters in the hepatic uptake and biliary excretion of valsartan, a selective antagonist of the angiotensin II ATl-receptor, in humans. Drug Metabolism and Disposition The Biological Fate of Chemicals, 34, 1247-1254. 

It s apparent that CYPs are involved in the metabolism of all but one, Plavix (clopido-grel), and even for that compound they re important downstream, after initial hydrolysis of the ester. What s not apparent from the figure is that metabolism isn t always something that limits drug effectiveness. Some drugs like valsartan are mostly excreted unchanged, while for others, like the top-seller Lipitor (atorvastatin) metabolism affords compounds that are still active. In Lipitor s case, active metabolites are said to account for 70% of the pharmacodynamic (PD) effect the drug produces. Much more worrisome would be reactive (electrophilic) metabolites that make for toxicity or metabolites that affect GYP expression or function. 

Fluconazole reduces the conversion of losartan to its active metabolite and decreases the metabolism of irbesartan, but the clinical relevance of these changes is uncertain. Fluconazole does not appear to influence the pharmacokinetics of eprosartan cande-sartan and valsartan. Itraconazole does not significantly affect the pharmacokinetics or antihypertensive effects of losartan, and ketoconazole does not affect the pharmacokinetics of eprosartan or losartan. 

Tetrazole derivatives are frequently used as metabolically stable surrogates for carboxylic acids (due to bioisosterism, cf. p. 274), as tetrazoles generally offer a more favorable pharmacokinetical profile [541]. Incorporation of tetrazole functionalities is especially found in antihypertensives (angiotensin II antagonists) of the sartan family, for example, irbesartan (37), losartan (38), and valsartan (39) [542] ... 

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