Kinetics of N-acetylprocainamide deacetylation

Area of Science:

• Pharmacokinetics
• Drug Metabolism
• Immunology

Background:

• N-acetylprocainamide (NAPA) is used clinically, often as an alternative to procainamide (PA).
• PA is known to induce a systemic lupus erythematosus-like reaction.
• NAPA has been reported to be safer immunologically than PA.

Purpose of the Study:

• To quantify the deacetylation of NAPA to PA in humans.
• To assess the clinical relevance of NAPA deacetylation in patients on long-term therapy.
• To evaluate the implications of NAPA deacetylation for its immunologic safety profile.

Main Methods:

• Utilized NAPA labeled with Carbon-13 (NAPA-13C) in the acetyl group to trace deacetylation.
• Determined deacetylation clearance (ClD) in a normal subject.
• Measured steady-state plasma ratios of PA to NAPA ([PA]/[NAPA]) in patients on long-term NAPA therapy.

Main Results:

• Deacetylation clearance (ClD) of NAPA was 6.5 ml/min, representing 2.8% of total NAPA elimination clearance (231 ml/min).
• The estimated ClD was representative of NAPA deacetylation rates in four patients on long-term NAPA therapy.
• Average steady-state [PA]/[NAPA] ratios were 0.024, potentially rising to 0.057 in anephric patients.

Conclusions:

• NAPA is metabolized to PA, its immunologically implicated precursor.
• The rate of NAPA deacetylation is low, suggesting a relative rather than absolute difference in immunologic safety compared to PA.
• Clinicians should consider the potential for PA formation from NAPA, especially in patients with renal impairment.