Dose-ranging effects of candoxatril on elimination of exogenous atrial natriuretic peptide in chronic heart failure.
Seven patients with chronic heart failure were treated in single-blind crossover fashion with placebo and 10 mg, 50 mg, and 200 mg doses of the neutral endopeptidase inhibitor candoxatril to determine the effects of candoxatril on the elimination kinetics of exogenously infused atrial natriuretic peptide (ANP). An incremental dose-response effect was observed on the mean maximum observed plasma concentration (Cmax) of the active metabolite candoxatrilat (107.4, 453.5, and 1584 ng/ml in response to 10, 50, and 200 mg candoxatril, respectively). Pooled active versus placebo comparisons showed that candoxatril reduced the clearance (p = 0.021) and elimination rate constant (p = 0.006) and increased Cmax (p = 0.002) and time to reach Cmax (p = 0.01) of exogenous ANP. Individually, both 50 mg and 200 mg but not 10 mg candoxatril significantly altered the elimination kinetics of ANP. The most favorable effects were observed in response to 200 mg candoxatril, although even this dose may not have achieved the maximal modulating effect on elimination of circulating ANP.
Motwani
J G
JG
Department of Clinical Pharmacology, Ninewells Hospital and Medical School, Dundee, Scotland.
Lang
C C
CC
Allen
M J
MJ
Johnson
H F
HF
Struthers
A D
AD
D000368:Aged; D000959:Antihypertensive Agents / Q000097:blood / Q000494:pharmacology*; D009320:Atrial Natriuretic Factor / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002303:Cardiac Output, Low / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007189:Indans / Q000097:blood / Q000494:pharmacology*; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology*; D011422:Propionates / Q000097:blood / Q000494:pharmacology*; D016037:Single-Blind Method
D000959:Antihypertensive Agents; D007189:Indans; D011355:Prodrugs; D011422:Propionates; D009320:Atrial Natriuretic Factor; C062766:candoxatril