Short-term
therapy with oral
hydralazine can favorably affect abnormal hemodynamics in patients with
congestive heart failure, but the range of dosage is large. To investigate whether this variability in effective dose is a result of altered systemic availability, we studied 10 patients with
congestive heart failure. Bioavailability (F) was calculated as the ratio of the blood AUC for a single 75 mg oral dose to the AUC of a 0.3 mg/kg iv dose. Acetylation capability was determined by
sulfamethazine metabolic clearance (CLsmz). The F value in six subjects with CLsmz greater than 100 ml/min was 9.9% +/- 6.0% (means +/- SD) and was lower than the value of 26.2% +/- 13.0% (P less than 0.05) in the four patients with CLsmz less than 60 ml/min. Thus acetylation ability is an important consideration during low-dose
hydralazine therapy (less than or equal to 225 mg/day). The clearance of the single intravenous dose of
hydralazine averaged 29.5 +/- 8.0 ml/min/kg, which is not different than that reported in populations without
heart failure. After oral dosage titration to induce maximum hemodynamic changes, the dose-normalized
hydralazine AUC rose from 53.5 +/- 50.5 to 247.2 +/- 213.4 min/L X 10(3). Thus large oral doses of
hydralazine result in disproportionate increases in systemic availability compatible with saturation of the first-pass effect or systemic clearance. In the doses required for maximum hemodynamic effects in our patients (225 to 3000 mg/day), this saturation phenomenon was a prominent determinant of systemic availability.