Hypertension Knowledge Centre
Angiotensin II Antagonists
Chemistry and pharmacokinetics of eprosartan
Chemistry
Eprosartan is a non-biphenyl, non-tetrazole AIIA, whereas all other AIIAs are biphenyl tetrazoles (losartan, candesartan, irbesartan, valsartan, telmisartan and olmesartan) (see figure 31).
Figure 31: Chemical structure of eprosartan (non-biphenyl, non-tetrazole) compared with other AIIAs (biphenyl tetrazoles)
Absorption
A single 300mg oral dose of eprosartan results in a bioavailability of approximately 13%.71 Plasma concentrations of eprosartan are proportional to dose within the range 100-200mg, but are less than proportional when 400 and 800mg doses are administered (figure 32).72 In the fasted state, peak plasma levels are reached 1-2 hours after oral dosing.72 Food delays absorption and T max by up to 1.7 hours, but this results in only minor changes (<25%) in C max and AUC,71 which are not of clinical consequence.
Figure 32: Plasma concentration curves following administration of single doses of eprosartan 100-800mg to healthy volunteers (n=23). Adapted from72
Distribution
Eprosartan has a high level of protein binding (approximately 98%), which is constant over the range of plasma concentrations achieved with therapeutic doses.73 Protein binding is unaffected by age, gender, hepatic dysfunction or mild-to-moderate renal impairment, but is lower in some patients with severe renal impairment.74,75 Eprosartan has a low volume of distribution (approximately 13 litres),71 indicating that it is not readily distributed to extravascular tissues.
Metabolism
Metabolism of eprosartan is negligible, and the compound is unchanged as it circulates around the body. Following oral and intravenous dosing with radiolabelled eprosartan, no metabolites are recovered from the plasma or faeces.76 In urine, approximately 20% of the radioactivity (corresponding to 2% of an oral dose and 7% of an intravenous dose) are excreted as an acyl glucuronide of eprosartan and the remaining 80% as unchanged drug.76 Eprosartan does affect hepatic P450 enzymes, thereby avoiding many potential drug interactions.
Elimination
Eprosartan has a total plasma clearance rate of about 130ml/min.71 Terminal half-life ranges between 5 and 9 hours in patients with mild-to-moderate hypertension. Biliary and renal routes are important in elimination.76 Following oral administration, 90% of the radioactivity is recovered in the faeces and 7% in the urine.76 Mean total recovery of the radioactive dose was approximately 98% for both routes of administration.
Drug interactions
Eprosartan has been shown not to inhibit human cytochrome P450 enzymes (CYP1A, CYP2A6, CYP2C9/8, CYP2C19, CYP2D6, CYP2E and CYP3A) in vitro at clinically relevant concentrations.77 This reduces the potential for drug interactions, so it may be given with other frequently prescribed drugs without interaction. Eprosartan has no effect on the pharmacokinetics of digoxin, warfarin, glibenclamide, ranitidine, fluconazole or ketoconazole.65
Eprosartan has been used concomitantly with thiazide diuretics (e.g. hydrochlorothiazide) and calcium channel blockers (e.g. sustained-release nifedipine) without evidence of clinically significant adverse interactions. It has been co-administered with hypolipidaemic agents (e.g. lovastatin, simvastatin, pravastatin, fenofibrate, gemfibrozil, niacin).
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. The possibility of a similar effect after the use of eprosartan can not be excluded and careful monitoring of serum lithium levels is recommended during concomitant use.65
Elderly patients
AUC and Cmax values are increased approximately two-fold in patients over 65 years of age compared with younger adults, and Tmax is longer.73 The elimination half-life of eprosartan in elderly subjects is approximately three hours longer than in younger patients with hypertension. However, no differences in the safety or efficacy of eprosartan have been observed in elderly compared with young patients with hypertension, and no dose adjustment is usually required.
Patients with renal impairment
Compared to subjects with normal renal function, mean AUC and Cmax were approximately 30% higher in patients with moderate renal impairment, and approximately 50% higher in patients with severe renal impairment.75 A daily dose not exceeding 600mg is recommended for patients with moderate or severe renal impairment (creatinine clearance <60ml/min). As expected for a compound that is highly protein bound, eprosartan is poorly removed by haemodialysis; the haemodialysis clearance rate is approximately 11ml/min.78
Hepatic impairment
The AUC (but not Cmax) of eprosartan increases by approximately 40% in patients with hepatic impairment compared with subjects with normal hepatic function.74 No dose adjustment is required in patients with hepatic impairment.
Please note that in some countries, dosage recommendations for the elderly and those with renal or hepatic impairment may vary from the above; please consult local prescribing information.