Kinetics of hydralazine elimination

Area of Science:

• Pharmacology
• Drug Metabolism
• Clinical Pharmacokinetics

Background:

• Hydralazine is an antihypertensive drug metabolized by acetylation.
• Individual differences in acetylation rates (slow vs. rapid) can affect drug pharmacokinetics.
• Understanding the dose-dependency of hydralazine metabolism is crucial for safe and effective use.

Purpose of the Study:

• To investigate the dose-dependency of hydralazine acetylation in humans.
• To determine if hydralazine acetylation is a saturable metabolic pathway.
• To correlate drug and metabolite concentrations in relation to acetylation capacity.

Main Methods:

• Oral administration of single hydralazine doses (10-150 mg) to slow and rapid acetylating subjects.
• Modified gas-liquid chromatography for simultaneous determination of hydralazine and its metabolite MTP in serum.
• Calculation of Area Under the Curve (AUC) ratios (AUC/dose and AUCMTP/AUChydralazine) over a 6-hour period.

Main Results:

• Higher doses (50 mg in slow, 150 mg in rapid acetylators) resulted in disproportionately increased hydralazine AUC/dose ratios.
• This increase was accompanied by a decrease in the ratio of acetylated metabolite (MTP) to parent drug (hydralazine) AUC.
• These findings suggest saturation of the hydralazine acetylation pathway at higher doses.

Conclusions:

• Hydralazine acetylation in humans is a capacity-limited process.
• The rate of acetylation becomes saturated at higher hydralazine doses.
• This saturation can lead to increased exposure to the parent drug, impacting its efficacy and safety profile.