Losartan metabolism

Both phenytoin and losartan are substrates for the cytochrome P450 isoenzyme CYP2C9. It appears that phenytoin had an inhibitory effect on losartan metabolism. The conversion of losartan to E3174 represents about 5 to 15% of the clearance of an oral losartan dose, but E3174 is much more active than losartan. 

Wang YH, Pan PP, Dai DP, Wang SH, Geng PW, Cai JP, Hu GX (2013) Effect of 36 CYP2C9 variants found in the Chinese population on losartan metabolism in vitro. Xenobiotica 44 270-275... 

Rifampin is known to induce the hepatic microsomal enzymes that metabolize various drugs such as acetaminophen, oral anticoagulants, barbiturates, benzodiazepines, beta blockers, chloramphenicol, clofibrate, oral contraceptives, corticosteroids, cyclosporine, disopyramide, estrogens, hydantoins, mexiletine, quinidine, sulfones, sulfonylureas, theophyllines, tocainide, verapamil, digoxin, enalapril, morphine, nifedipine, ondansetron, progestins, protease inhibitors, buspirone, delavirdine, doxycycline, fluoroquinolones, losartan, macrolides, sulfonylureas, tacrolimus, thyroid hormones, TCAs, zolpidem, zidovudine, and ketoconazole. The therapeutic effects of these drugs may be decreased. 

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).]... 

B) Increased metabolism of losartan due to induction of CYP2C9 by rofecoxib... 

Losartan potassium is well tolerated. Bioavailability is 33% due to hepatic first pass metabolism. It is 98% plasma protein bound. It is activated in liver. Both parent compound and active compound are excreted in urine. 

In view of their incomplete oral bioavailability, several CYP2C substrates may undergo significant first-pass intestinal metabolism, including the CYP2C9 substrates verapamil (155), losartan (156), fluvastatin (157), and diclofenac (158), and the CYP2C19 substrates (5)-mephenytoin (159) and omeprazole... 

Lee CR, Pieper JA, Reginald FF et al (2003) Tolbutamide, flurbiprofen and losartan as probes of CYP2C9 activity in humans. J Clin Pharmacol 43 84—91 Miners JO, Birkett DJ (1998) Cytochrome P4502C9 an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol 45 525-538... 

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... 

Kaukonen KM, Olkkola KT, Neuvonen PJ. Fluconazole but not itraconazole decreases the metabolism of losartan to E-3174. Eur J Clin Pharmacol 1998 53(6) 445-9. 

Bioprecursors do not imply a temporary linkage between the active principle and a carrier group, but result from a molecular modification of the active principle itself. This modification generates a new compound, which is a substrate for metabolizing enzymes, leading to a metabolite that is the expected active principle. This approach exemplifies the active metabolite concept in a provisional way (e.g. sulindac, fenbufen, acyclovir, losartan). 

ACE inhibitors prevent the conversion of angiotensin I to angiotensin II and lower blood pressure by decreasing both the formation of aldosterone formation and the vasoconstrictive action of AH at AT-1 receptors. ACEIs also inhibit the metabolism of bradykinin, and this leads to additional hypotensive effects, because bradykinin is an endogenous vasodilator. Unfortunately, increases in bradykinin are associated with side effects, including cough and angioedema. Losartan, which blocks AT-1 receptors, does not increase bradykinin levels. 

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