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Metabolism of the vasodilator hydralazine was investigated by in vivo and in vitro studies. Standards to identify metabolic products were synthesized. Determination and quantification of hydralazine and its metabolites were accomplished by gas chromatography-mass spectrometry. A deuterium-labeled internal standard was used for quantification. 14C-labeled internal standards were synthesized and used to demonstrate recoveries from the biological samples.

Six male hypertensive patients, three rapid and three slow acetylators, each received four different intravenous hydralazine doses by constant infusion over 100 sec. Two to four days elapsed between doses. Plasma or whole-blood hydralazine concentrations were measured by HPLC after each dose. There was no influence of acetylator phenotype on hydralazine kinetics after intravenous dosing. There also was no consistent effect of dose size on hydralazine clearance or volume of distribution at doses up to 0.45 mg (2.3 mumol/kg). One subject, who received doses up to 0.6 mg/kg (3.05 mumol), had an apparent decrease in clearance at the higher doses. These findings are consistent with the fact that hydralazine is converted intravascularly to hydralazine pyruvic acid hydrazone and the fact that potentially saturable hepatic metabolic pathways play only a modest role in systemic clearance.

The efficacy and toxicity of hydralazine differ widely among individual patients, possibly because of different sensitivities to drug effect or as a reflection of pharmacokinetic differences. Therefore, the variability in plasma hydralazine concentrations after single intravenous and single and multiple oral doses was studied in 9 male hypertensive patients. After an intravenous dose of 0.3 mg/kg the area under the plasma concentration time curve (AUC) varied over less than a twofold range 17.5-29.5 muM-minute. However, after a single oral dose, 1 mg/kg, and after at least the fifth dose of a regimen consisting of 1 mg/kg given every 12 hours, there were much wider variations in AUC values: 4.0-30.4 and 3.2-38.5 muM-minute, respectively. Similar ranges in peak hydralazine concentration, Cp, were also noted, 0.12-1.31 muM after single oral dose and 0.10-1.39 muM after the multiple dose regimen. A significant portion of the observed interpatient variability could be explained by differences in acetylation ability. The AUC and Cp values for both the single and multiple oral doses were significantly lower (P less than 0.001) in rapid than in slow acetylators. Therefore, determining the acetylation ability of patients requiring hydralazine may help to optimize therapeutic benefit and minimize toxicity.

A specific high-performance liquid chromatographic assay for hydralazine in human plasma was developed. Plasma hydralazine is reacted with 10 microliter of p-anisaldehyde for 7 min at room temperature to form hydralazine p-anisaldehyde hydrazone. This derivative is extracted into ethyl acetate, and the solvent is removed by evaporation. The residue is reconstituted in 100 microliter of methanol, and 90 microliter is injected onto a reversed-phase column. The mobile phase is 32% acetonitrile in 0.75 M acetate buffer, pH 3.4, at a flow rate of 2 ml/min. The retention time of hydralazine p-anisaldehyde hydrazone is 6.5 min. The average coefficient of variation over 10-200 ng/ml is 5.5%, and the sensitivity limit is 5 ng/ml. Under the assay conditions, hydralazine pyruvic acid hydrazone, a known plasma metabolite of hydralazine, yields less than 0.1% hydralazine. Detectable plasma hydralazine levels of 5-20 ng/ml were found 10-30 min after a 0.5-mg/kg oral dose of hydralazine hydrochloride was given to a male volunteer.