ABSOLUTE BIOAVAILABILITY AND PHARMACOKINETICS OF VALSARTAN, AN ANGIOTENSIN-II RECEPTOR ANTAGONIST, IN MAN

Objective: The pharmacokinetics of orally and intravenously administer ed valsartan were determined in two studies. In a first pilot study, t hree i.v. doses of valsartan were given in an ascending manner (5, 10 and 20 mg) to evaluate tolerability and basic pharmacokinetics of the i.v. formulation. In a second study, the absolute bioavailability of 8 0 mg valsartan from a capsule and a buffered solution was compared wit h a 20 mg i.v. dose. Methods: The concentrations of valsartan in plasm a and urine were measured using HPLC. The disposition of valsartan aft er an i.v. dose was characterized by biphasic decay kinetics, with a d istribution phase (half-life 1.0 h), followed by a longer elimination phase (half-life 9.5 h). The volume of distribution al steady state wa s 16.9 l, and the total body clearance 2.2 l.h(-1). 29% of the i.v. do se was recovered unchanged in the urine. Results: Plasma levels peaked 2 h after oral administration of the 80 mg capsule. Thereafter, plasm a levels declined biexponentially with a terminal t(1/2) of 7.0 h. C-m ax was reached 1 h after administration of the solution, and t(1/2) wa s 7.5 h. On average 7.3% (capsule) and 12.6% (solution) of the dose wa s excreted in the urine as the unchanged drug. The fraction of dose ab sorbed and systemically available after oral administration was 0.23 f or the capsule and 0.39 for the solution, based on AUC. Absorption app eared to follow two first-order processes. The first phase was rapid, with a half-life of 0.5 h and 0.9 h for solution and capsule, respecti vely. The slower absorption phase was characterized by a half-life of 6.5 h for the solution and 3.5 h for the capsule. Most of the drug was absorbed during the period 0.4 h to 3 h post-dosing, and 90% of the f raction absorbed from the capsule was absorbed within 5 h.