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 effec ts of candoxatril on the elimination kinetics of exogenously infused a trial natriuretic peptide (ANP). An incremental dose-response effect w as observed on the mean maximum observed plasma concentration (C(max)) of the active metabolite candoxatrilat (107.4, 453.5, and 1584 ng/ml in response to 10, 50, and 200 mg candoxatril, respectively). Pooled a ctive versus placebo comparisons showed that candoxatril reduced the c learance (p = 0.021) and elimination rate constant (p = 0.006) and inc reased C(max) (p = 0.002) and time to reach C(max) (p = 0.01) of exoge nous ANP. Individually, both 50 mg and 200 mg but not 10 mg candoxatri l significantly altered the elimination kinetics of ANP. The most favo rable effects were observed in response to 200 mg candoxatril, althoug h even this dose may not have achieved the maximal modulating effect o n elimination of circulating ANP.