Hemodynamic and humoral effects of the new renin inhibitor enalkiren in normal humans.
The effect of the renin inhibitor enalkiren (Abbott-64662) was evaluated in eight normal volunteer subjects on a standardized sodium diet (100 mmol/day) by measurement of various components of the renin-angiotensin system and drug levels in plasma. On day 1, vehicle and doses of 0.001, 0.003, and 0.01 mg/kg i.v. were administered within 2 minutes at 90-minute intervals. On day 2, vehicle and doses of 0.01, 0.03, and 0.1 mg/kg i.v. were given. With the higher doses, blood pressure tended to decrease slightly with no change in heart rate. Plasma renin activity and plasma angiotensin-(1-8)octapeptide (angiotensin II) fell markedly in a dose-dependent manner. Inhibition of plasma renin activity was maximal 5 minutes after administration of the drug and persisted 90 minutes after the doses of 0.03 and 0.1 mg/kg. Not surprisingly, there was a close correlation between plasma renin activity and plasma angiotensin II levels (r = 0.81, n = 28, p less than 0.001). In contrast, active and total renin measured directly by monoclonal antibodies rose in dose-related fashion in response to renin inhibition. Pharmacokinetic parameters were calculated using the plasma drug concentrations obtained up to 6 hours after the 0.1 mg/kg dose. By means of a two-compartment model, plasma mean half-life of the drug was estimated at 1.60 +/- 0.43 hours.
Delabays
A
A
Division of Hypertension, University Hospital, Lausanne, Switzerland.
Nussberger
J
J
Porchet
M
M
Waeber
B
B
Hoyos
P
P
Boger
R
R
Glassman
H
H
Kleinert
H D
HD
Luther
R
R
Brunner
H R
HR
D000328:Adult; D000804:Angiotensin II / Q000097:blood; D004151:Dipeptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D007275:Injections, Intravenous; D012016:Reference Values; D012083:Renin / Q000097:blood; D000092502:Renin Inhibitors
D000804:Angiotensin II; D004151:Dipeptides; D012083:Renin; D000092502:Renin Inhibitors; C056622:enalkiren