Inhibition of N‐Acetylation of Procainamide and Renal Clearance of N‐Acetylprocainamide by Para‐Aminobenzoic Acid in Humans

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Abstract
Procainamide administration often results in excessively high serum N‐acetylprocainamide (NAPA) concentrations and subtherapeutic serum procainamide concentrations. Inhibition of N‐acetylation of procainamide may prevent accumulation of excessive NAPA while maintaining therapeutic serum procainamide concentrations. The purpose of this randomized, two‐way crossover study was to determine if para‐aminobenzoic acid (PABA) inhibits N‐acetylation of procainamide in healthy volunteers. Eleven (7 female, 4 male) fast acetylators of caffeine received, in random order, PABA 1.5 g orally every 6 hours for 5 days, with a single intravenous dose of procainamide 750 mg administered over 30 minutes on the third day, or intravenous procainamide alone. Blood samples were collected during a 48‐hour period after initiation of the infusion. Urine was collected over a 72‐hour period. Serum procainamide and NAPA concentrations were analyzed using fluorescence polarization immunoassay. Urine procainamide and NAPA concentrations were measured with high performance liquid chromatography. PABA did not significantly influence total or renal procainamide clearance, elimination rate constant, AUC0‐∞, amount of procainamide excreted unchanged in the urine, or volume of distribution. However, concomitant PABA administration with procainamide resulted in increases in NAPA AUC0‐∞ and t1/2 and reductions in NAPA Ke, procainamide acetylation (NAPA formation) clearance, and NAPA renal clearance. Although PABA inhibits metabolic conversion of procainamide to NAPA, it also impairs the renal clearance of NAPA (but not procainamide) in healthy subjects. Therefore, PABA may not be useful for optimizing the safety or efficacy of procainamide in patients.