Hydralazine kinetics after single and repeated oral doses

Area of Science:

• Pharmacokinetics
• Analytical Chemistry
• Clinical Pharmacology

Background:

• Previous hydralazine assays overestimated plasma levels due to cross-reactivity with metabolites.
• Accurate measurement of hydralazine and its metabolites is crucial for understanding its pharmacokinetics.

Purpose of the Study:

• To develop and validate specific assay methods for hydralazine and its major metabolite, hydralazine pyruvic acid hydrazone (HPH).
• To determine the pharmacokinetic profiles of hydralazine and HPH in hypertensive patients.
• To investigate the influence of acetylator phenotype on hydralazine bioavailability and kinetics.

Main Methods:

• Development of specific, sensitive assay methods for hydralazine and HPH.
• Determination of hydralazine and HPH plasma levels after single and repeated oral doses.
• Kinetic analysis based on acetylator phenotype (fast vs. slow).

Main Results:

• Hydralazine bioavailability was significantly higher in slow acetylators (31.3% single, 39.3% repeated dose) compared to fast acetylators (9.5% single, 6.6% repeated dose).
• Peak plasma levels were lower than previously reported with nonspecific assays and varied by acetylator phenotype.
• No significant alteration in kinetics or plasma accumulation of hydralazine was observed upon repeated dosing.
• HPH levels were proportional to hydralazine levels and 2.5-4 times higher.
• HPH accumulated in fast acetylators but not in slow acetylators after repeated hydralazine doses.
• Elimination half-lives for hydralazine were independent of acetylator phenotype (4-6 hours).

Conclusions:

• Specific assays provide accurate measurements of hydralazine and HPH, revealing phenotype-dependent bioavailability.
• Hydralazine pharmacokinetics are influenced by acetylator status, impacting drug efficacy and dosing strategies.
• Understanding HPH kinetics is important, particularly its accumulation in fast acetylators with repeated dosing.