Determinants of systemic availability of oral hydralazine in heart failure

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 (CL smz ). The F value in six subjects with CL smz >100 ml/min was 9.9% ± 6.0% (X̄ ± SD) and was lower than the value of 26.2% ± 13.0% (P < 0.05) in the four patients with CL smz <60 ml/min. Thus acetylation ability is an important consideration during low‐dose hydralazine therapy (≤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 × 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. Clinical Pharmacology and Therapeutics (1985) 38, 538–543; doi: 10.1038/clpt.1985.220