Identification of cytochrome P450 forms involved in the 4-hydroxylation of valsartan, a potent and specific angiotensin II receptor antagonist, in human liver microsomes

Abstract

Valsartan is known to be excreted largely as unchanged compound and is minimally metabolized in man. Although the only notable metabolite is 4-hydroxyvaleryl metabolite (4-OH valsartan), the responsible enzyme has not been clarified at present. The current in vitro studies were conducted to identify the cytochrome P450 (CYP) enzymes involved in the formation of 4-OH valsartan. Valsartan was metabolized to 4-OH valsartan by human liver microsomes and the Eadie-Hofstee plots were linear. The apparent Km and Vmax values for the formation of 4-OH valsartan were 41.9-55.8 microM and 27.2-216.9 pmol min(-1) mg(-1) protein, respectively. There was good correlation between the formation rates of 4-OH valsartan and diclofenac 4'-hydroxylase activities (representative CYP2C9 activity) of 11 individual microsomes (r = 0.889). No good correlation was observed between any of the other CYP enzyme marker activities (CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP4A). Among the recombinant CYP enzymes examined (CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4, 3A5 and 4A11), CYP2C9 notably catalysed 4-hydroxylation of valsartan. For the specific CYP inhibitors or substrates examined (furafylline, diclofenac, S(+)-mephenytoin, quinidine and troleandomycin), only diclofenac inhibited the formation of 4-OH valsartan. These results showed that CYP2C9 is the only form responsible for 4-hydroxylation of valsartan in human liver microsomes. Although CYP2C9 is involved in valsartan metabolism, CYP-mediated drug-drug interaction between valsartan and other co-administered drugs would be negligible.

Lack of Pharmacokinetic Interactions Between Dapagliflozin and Simvastatin, Valsartan, Warfarin, or Digoxin

“…Valsartan is minimally metabolized in humans, with no involvement of CYP isozymes [23]. In addition, there is no evidence to indicate that its rapid absorption is affected by P-gp.…”

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

“…The primary metabolite, accounting for 9% of administered dose, is valeryl-4-hydroxy valsartan, which is generated by CYP2C9 (Nakashima et al, 2005). Valsartan did not inhibit P450 enzymes to a clinically relevant extent in vitro (Taavitsainen et al, 2000) and, even in very high concentrations, did not inhibit CYP2C9 function .…”

Evaluation of the Relationship between Sex, Polymorphisms in CYP2C8 and CYP2C9, and Pharmacokinetics of Angiotensin Receptor Blockers

“…Losartan is primarily metabolized by CYP2C9 via an aldehyde intermediate (E-3179) to the pharmacologically active 5-carboxylic acid metabolite E-3174 (Israili, 2000;Yasar et al, 2002;Lee et al, 2003). Candesartan and valsartan are metabolized to pharmacologically inactive metabolites, albeit slowly, by the action of CYP2C9 (Waldmeier et al, 1997;McClellan and Goa, 1998;Schmidt and Schieffer, 2003;Nakashima et al, 2005). Telmisartan (Telmisartan Alter, Micardis) has no affinity for any of the cytochrome P450 (P450) isoenzymes (Unger and Kaschina, 2003), including CYP2C9, and is partially metabolized by glucuronidation (Israili, 2000).…”