Absolute bioavailability and pharmacokinetics of the angiotensin II receptor antagonist fimasartan in healthy subjects

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%.

Angiotensin receptor blockers (ARBs) is an effective and well tolerated first-line antihypertensive drug. Fimasartan is a newly developed ARB that has not been compared with other ARBs with regard to its efficacy and tolerability.

CS-866, a novel angiotensin II receptor blocker, is rapidly and completely metabolized to RNH-6270, its active metabolite. The pharmacokinetics of RNH-6270 following oral CS-866 or intravenous RNH-6270 administration was determined in 104 healthy male volunteers. The pharmacokinetics of RNH-6270 was linear over dose ranges of 1 to 32 mg (intravenous RNH-6270 administration) and 10 to 160 mg (oral CS-866 administration). The time to maximum plasma concentration of RNH-6270 after oral CS-866 administration ranged from 1.4 to 2.8 hours, and the terminal elimination half-life ranged from 12 to 18 hours. Absolute bioavailability of RNH-6270 after oral administration of CS-866 was 26%. Administration of CS-866 once daily for 10 days did not result in drug accumulation. When administered intravenously, RNH-6270 has a volume of distribution of 15 to 25 L. Approximately 35% to 50% of RNH-6270 is excreted unchanged in the urine. CS-866 was safe and well tolerated at doses of up to 160 mg/day.