The influence of dietary protein deficiency on the disposition of procainamide (PA) and its major metabolite, N-acetylprocainamide (NAPA) was investigated in male Sprague-Dawley rats fed for 4 weeks on a 23 (control) or a 5% (low) protein diet ad libitum. Procainamide and N-acetylprocainamide in plasma and urine were determined by a sensitive and specific HPLC assay using a cation-exchange column. After an iv dose of 50 mg/kg procainamide hydrochloride, the average mean residence time (MRT) was approximately 82% higher, while the total plasma clearance (CI) per kg of body weight and terminal elimination rate constant (k) were significantly decreased by 46 and 49%, respectively, in the protein-deficient animals. No significant differences were found in the two groups of animals with respect to the apparent steady state volume of distribution (Vss). Although the percentage of PA recovered unchanged in the urine over 48 hr was not significantly different between control and protein-deficient animals, rats on a low protein diet excreted a smaller percentage of the administered PA dose (mean +/- SE, 19.0 +/- 4.0 vs. 30.8 +/- 1.4%) as NAPA. In addition to the apparent decrease in metabolic clearance (CIm) to NAPA (6.8 +/- 1.4 vs. 19.9 +/- 2.3 ml/min/kg) in the protein-deficient rats, there was a 55% decrease in the renal clearance of PA. There appeared to be no significant difference in the disposition characteristics of NAPA (i.e. MRT, Vss, CI, and k) between the two groups of animals after a 25 mg/kg dose of N-acetylprocainamide hydrochloride.(ABSTRACT TRUNCATED AT 250 WORDS)