Pharmacokinetics of losartan, an angiotensin II receptor antagonist, and its active metabolite EXP3174 in humans

Abstract

The pharmacokinetics of the angiotensin II receptor antagonist losartan potassium and its active carboxylic acid metabolite EXP3174 were characterized in 18 healthy male subjects after administration of intravenous losartan, intravenous EXP3174, and oral losartan. In these subjects, the average plasma clearance of losartan was 610 ml/min, and the volume of distribution was 34 L. Renal clearance (70 ml/min) accounted for 12% of plasma clearance. Terminal half-life was 2.1 hours. In contrast, the average plasma clearance of EXP3174 was 47 ml/min, and its volume of distribution was 10 L. Renal clearance was 26 ml/min, which accounted for 55% of plasma clearance; terminal half-life was 6.3 hours. After oral administration of losartan, peak concentrations of losartan were reached in 1 hour. Peak concentrations of EXP3174 were reached in 3 1/2 hours. The area under the plasma concentration-time curve of EXP3174 was about four times that of losartan. The oral bioavailability of losartan tablets was 33%. The low bioavailability was mainly attributable to first-pass metabolism. After intravenous or oral administration of losartan the conversion of losartan to the metabolite EXP3174 was 14%.

Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension

“…14,15,135 The T max (Table 6a) of losartan and EXP3174 are 1-1.3 h and 3-6 h, respectively. 14,15,[132][133][134] Systemic bioavailability of losartan is 33% (range = 29-43%). [132][133][134] About 14% of an oral or intravenous dose of losartan is converted to EXP3174.…”

“…14,15,[132][133][134] Systemic bioavailability of losartan is 33% (range = 29-43%). [132][133][134] About 14% of an oral or intravenous dose of losartan is converted to EXP3174. 14,15,133,134 The C max and AUC of losartan and EXP3174 are linearly related to the dose of losartan (25-200 mg).…”

“…[132][133][134] About 14% of an oral or intravenous dose of losartan is converted to EXP3174. 14,15,133,134 The C max and AUC of losartan and EXP3174 are linearly related to the dose of losartan (25-200 mg). 18 The C max AUC of EXP3174 is two to four times higher than for losartan.…”

“…18 The C max AUC of EXP3174 is two to four times higher than for losartan. 18,[132][133][134] Food delays the absorption of losartan and lowers its C max , but the AUC of losartan or EXP3174 are not significantly altered. 14,15,132 Losartan and EXP3174 are highly bound (Table 6a) to plasma proteins (98.7% and 99.8%, respectively), primarily to albumin.…”

“…14,15,135 The apparent Vd of losartan and EXP3174 is in the range of 28-47 L and 10-12 L, respectively. 14,15,133,134 The Cl T of losartan and EXP3174 is about 600 mL/min and 50 mL/min, respectively (Table 6b). 14,15,133,134 Plasma elimination t .…”