Is losartan (an angiotensin II receptor antagonist) primarily eliminated by the kidneys or the liver?

From the Guidelines

Losartan is primarily eliminated by the liver, with a significant portion of its metabolism occurring through the cytochrome P450 enzyme system, specifically CYP2C9 and CYP3A4, as indicated in the context of its pharmacokinetics 1. The liver metabolizes losartan to an active metabolite (EXP-3174) that provides much of the drug's angiotensin II receptor blocking activity. This hepatic metabolism means that patients with liver impairment may require dosage adjustments due to potentially increased drug exposure. However, the kidneys do play a secondary role in elimination, as they excrete both the metabolites and the small amount of unchanged drug, with recommendations for its use in chronic kidney disease suggesting monitoring of electrolyte balance and serum creatinine 1. Key points to consider include:

• Losartan's primary elimination pathway is hepatic, involving the cytochrome P450 system.
• The drug is recommended for the treatment of hypertension or renal failure in type 2 diabetes with microalbuminuria at doses of 50–100 mg/day, with regular monitoring of electrolyte balance and serum creatinine 1.
• While the liver is the primary site of losartan elimination, renal function also plays a role in the excretion of its metabolites and unchanged drug, particularly in cases of severe renal dysfunction.

From the FDA Drug Label

After single doses of losartan administered orally, about 4% of the dose is excreted unchanged in the urine and about 6% is excreted in urine as active metabolite. Biliary excretion contributes to the elimination of losartan and its metabolites Following oral 14C-labeled losartan, about 35% of radioactivity is recovered in the urine and about 60% in the feces.

Losartan is eliminated by both the kidney and liver. The drug is excreted in the urine and also undergoes biliary excretion, which contributes to its elimination. Approximately 35% of the radioactivity is recovered in the urine, while about 60% is recovered in the feces, indicating that both renal and hepatic pathways are involved in the elimination of losartan and its metabolites 2.

From the Research

Elimination of Losartan

• Losartan is primarily eliminated by the liver, with the major metabolic pathway being through the cytochrome P450 (CYP) 3A4, 2C9, and 2C10 isoenzymes 3, 4.
• The liver metabolizes losartan to its active metabolite, E 3174, which is 10- to 40-fold more potent than losartan 3.
• The kidneys play a role in eliminating losartan and its metabolite, with renal clearance accounting for 12% of plasma clearance for losartan and 55% for E 3174 5.
• Losartan is not significantly removed by haemodialysis, indicating that the kidneys do not play a major role in its elimination 3.

Role of the Liver in Losartan Metabolism

• The liver is responsible for converting losartan to its active metabolite, E 3174, through the CYP3A4 enzyme 4.
• The liver's role in losartan metabolism is supported by studies showing that losartan is metabolized by human liver microsomes and purified cytochrome P450 enzymes 4.
• Although rare, losartan can cause drug-induced liver injury, highlighting the importance of monitoring liver function in patients taking this medication 6.

Comparison of Liver and Kidney Elimination

• The liver is the primary organ responsible for eliminating losartan, with the kidneys playing a secondary role 3, 5.
• The renal clearance of losartan is relatively low, accounting for only 12% of plasma clearance, whereas the liver's metabolic clearance is much higher 5.