Eprosartan

Eprosartan is a potent, synthetic, orally active non-biphenyl non-tetrazole angiotensin II receptor antagonist, which binds selectively to the AT₁ receptor.

Angiotensin II is a potent vasoconstrictor and the primary active hormone of the renin-angiotensin-aldosterone system, playing a major part in the pathophysiology of hypertension.

Absorption

Absolute bioavailability following a single 300 mg oral dose of eprosartan is about 13%, due to limited oral absorption. Eprosartan plasma concentrations peak at one to two hours after an oral dose in the fasted state. Plasma concentrations are dose proportional from 100 to 200 mg, but less than proportional for 400 and 800 mg doses. A slight accumulation (14%) is seen with chronic use of eprosartan. Administration of eprosartan with food delays absorption with minor increases (<25%) observed in C_max and AUC.

Distribution

The volume of distribution of eprosartan is about 13 litres. Plasma protein binding of eprosartan is high (approximately 98%) and constant over the concentration range achieved with therapeutic doses. The extent of plasma protein binding is not influenced by gender, age, hepatic dysfunction or mild-moderate renal impairment but has shown to be decreased in a small number of patients with severe renal impairment.

Biotransformation and elimination

Following intravenous [¹⁴C] eprosartan, about 61% of radioactivity is recovered in the faeces and about 37% in the urine. Following an oral dose of [¹⁴C] eprosartan, about 90% of radioactivity is recovered in the faeces and about 7% in the urine.

Following oral and intravenous dosing with [¹⁴C] eprosartan in human subjects, eprosartan was the only drug-related compound found in the plasma and faeces. In the urine, approximately 20% of the radioactivity excreted was an acyl glucuronide of eprosartan with the remaining 80% being unchanged eprosartan.

The terminal elimination half-life of eprosartan following oral administration is typically five to nine hours. Total plasma clearance is about 130 ml/min. Biliary and renal excretion contribute to the elimination of eprosartan.

Special populations

Geriatric patients

Both AUC and C_max values of eprosartan are increased in the elderly (on average, approximately two-fold), but this does not necessitate alterations in dosing.

Hepatically impaired patients

Following administration of a single 100 mg dose of eprosartan, AUC values of eprosartan (but not C_max) are increased, on average, by approximately 40% in patients with hepatic impairment.

Renally impaired patients

Compared to subjects with normal renal function (n=7), mean AUC and C_max values were approximately 30% higher in patients with creatinine clearance 30-59 ml/min (n=11) and approximately 50% higher in patients with creatinine clearance 5-29 ml/min (n=3).

In a separate investigation, mean AUC was approximately 60% higher in patients undergoing dialysis (n=9) compared to subjects with normal renal function (n=10).

Gender

There is no difference in the pharmacokinetics of eprosartan between males and females.

Acute toxicity

There were no mortalities in rats and mice dosed at up to 3000 mg/kg BW and in dogs given up to 1000 mg/kg BW.

Chronic toxicity

In chronic toxicity studies eprosartan did not produce any toxic effects in rats (after oral administration of doses of up to 1000 mg/kg/day for up to six months). In dogs, eprosartan caused a reduction in red cell parameters (erythrocytes, haemoglobin, haematocrit) at doses of 30 mg/kg BW/day or more after oral administration for up to six months, but red cell parameters returned to normal values at 1 year despite continuous drug administration.

Reproductive and developmental toxicity

In pregnant rabbits, eprosartan has been shown to produce maternal and foetal mortality at 10 mg/kg BW per day during late pregnancy only. Maternal toxicity but no foetal effects were observed at 3 mg/kg BW per day.

Genotoxicity

Genotoxicity was not observed in a battery of in vitro and in vivo tests

Carcinogenicity

Carcinogenicity was not observed in rats and mice given up to 600 or 2000 mg/kg BW per day respectively for 2 years.