Effects of Ofloxacin on the Pharmacokinetics and Pharmacodynamics of Procainamide

Abstract

Procainamide is a class I antiarrhythmic agent that undergoes active tubular secretion through the organic cation transport system, with approximately 50% of a dose excreted in the urine as unchanged drug. The remainder is metabolized to an active metabolite, n-acetyl procainamide (NAPA). Ofloxacin is a fluoroquinolone antibiotic that is excreted in the urine as unchanged drug via active tubular secretion and glomerular filtration. To test the hypothesis that ofloxacin may interfere with the renal elimination of procainamide, 9 healthy volunteers were randomly assigned to receive 1 g of oral procainamide as a single dose with or without pretreatment with 400 mg of ofloxacin twice a day for 5 doses. Blood and urine samples were obtained and pharmacokinetic parameters for procainamide were determined for each treatment period. Standard 12-lead and signal-averaged electrocardiographic recordings were used for pharmacodynamic analysis. The mean area under the concentration-time curve (AUC) and peak plasma concentration (Cmax; mug/mL) for procainamide increased by 27% and 21%, respectively, and the plasma clearance for procainamide decreased by an average of 22% with coadministration of ofloxacin. Ofloxacin did not significantly influence the pharmacokinetics of NAPA, nor were pharmacodynamics of procainamide significantly affected by coadministration of ofloxacin. These results suggest that procainamide concentrations should be monitored closely when coadministered with ofloxacin.

Membrane Transport Mechanisms of Quinidine and Procainamide in Renal LLC-PK1 and Intestinal LS180 Cells

“…1,7,8) When transcellular drug transport is examined under the condition where the unlabeled drug concentration in the monolayer is equilibrated with that of the incubation medium in the apical and basolateral chambers, transport data for a small amount of radiolabeled drug can be analyzed using the linear pharmacokinetic model. That is, the following mass balance equations were prepared for pharmacokinetic analysis: (1) (2) (3) where X A , X B , and X C are the amounts of radio-labeled drugs in the apical chamber, basolateral chamber, and monolayer determined at time t, respectively. V A and V B indicate the volume of the apical chamber (0.75 ml) and the basolateral chamber (1.5 ml), respectively.…”

“…4) The Kp (octanol/buffer at pH 7.4) value of procainamide is about 0.1, and approximately half of the dose is excreted in the urine as unchanged drug. [3][4][5][6] However, the mechanisms responsible for the membrane transport of procainamide in intestinal and renal epithelial cells are still unclear.…”

Levofloxacin and Ciprofloxacin Decrease Procainamide and N -Acetylprocainamide Renal Clearances

“…Procainamide and NAPA concentrations were measured by using a fluorescence polarization immunoassay (Abbott Diagnostics, Irving, Tex.) with interday coefficients of variation of Ͻ8% at 10 mg/liter (4,5,15). Creatinine concentrations were measured by using a kinetic alkaline picrate assay (Beckman Coulter, Inc., Fullerton, Calif.) with interday coefficients of variation of Ͻ5% at 0.5, 5, and 50 mg/dl.…”

“…Procainamide, N-acetylprocainamide (NAPA; the active metabolite of procainamide), and several fluoroquinolone antibiotics are eliminated renally by active tubular secretion (9,11,15,16,21). Procainamide serum concentrations increase and its pharmacokinetics change due to concurrent therapy with ofloxacin (15).…”

“…Procainamide, N-acetylprocainamide (NAPA; the active metabolite of procainamide), and several fluoroquinolone antibiotics are eliminated renally by active tubular secretion (9,11,15,16,21). Procainamide serum concentrations increase and its pharmacokinetics change due to concurrent therapy with ofloxacin (15). The purpose of this study was to investigate the possibility of a renal drug interaction between procainamide and levofloxacin, one of the stereoisomers of ofloxacin.…”