Levofloxacin and Ciprofloxacin Decrease Procainamide and N -Acetylprocainamide Renal Clearances

Abstract

Ten healthy adults participated in a randomized, crossover drug interaction study testing procainamide only, procainamide plus levofloxacin, and procainamide plus ciprofloxacin. During levofloxacin therapy, most procainamide and N-acetylprocainamide (NAPA) pharmacokinetic parameters, including decreased renal clearances and renal clearance/creatinine clearance ratios, changed (P < 0.05). During ciprofloxacin treatment, only procainamide and NAPA renal clearances decreased significantly.Renal drug interactions in patients are often overlooked when new drug therapy is added to existing therapeutic regimens. 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. For comparison, the potential for a ciprofloxacin-procainamide drug interaction was also studied.(A portion of this work was presented in abstract form at the 2001 American College of Clinical Pharmacology Annual Meeting, Tampa, Fla.)Ten healthy adults (five males, five females; ages, 21 to 35 years; weights, 52 to 87 kg; seven Caucasians, three Asians) participated in the study. The investigation was approved by the university human subjects committee, and subjects provided written informed consent. All individuals had normal physical examinations, laboratory screening tests (serum electrolytes, renal and liver function tests, and complete blood cell counts), and 12-lead electrocardiograms. Subjects were within 20% of their ideal body weight, did not smoke tobacco-containing products, had no known allergy to study medications, took no additional medications, and, if female, had negative serum pregnancy tests (6). Beverages containing alcohol or methylxanthines were not allowed during the study period.The study was a three-way randomized, controlled trial designed to investigate a potential drug interaction between procainamide and two fluoroquinolone antibiotics. Subjects were not blinded from antibiotic study drugs because of obvious differences in dosage forms and administration schedules. Each of the following procedures was performed with procainamide alone (control phase) or on the fifth day of fluoroquinolone oral administration (500 mg of levofloxacin every day at 0800 h and 500 mg of ciprofloxacin every 12 h at 0800 h and 2000 h). Prior to admission to the Clinical Research Center for administration of procainamide, subjects were allowed to selfadminister the fluoroquinolone at home; compliance was assured by inspection of a medication administration diary, tablet counts of doses remaining in the pill vial, and subject interviews by investigators. In order for the study to proceed, all drug doses needed to be administered within 15 ...

Human Organic Cation Transporters 1 ( SLC22A1 ), 2 ( SLC22A2 ), and 3 ( SLC22A3 ) as Disposition Pathways for Fluoroquinolone Antimicrobials

“…As shown in Table 1, all DDI index values were found to be below the cutoff value of 0.1, suggesting that any hOCT1 or hOCT3 inhibition by these FQs is unlikely to result in any clinically relevant DDIs. Nevertheless, FQ-transporter-based drug interactions may gain clinical importance where there exist genetic or environmental differences associated with drug-metabolizing enzyme and/or drug transporter phenotypes affecting the pharmacokinetics and resultant pharmacodynamics of the interacting drugs (16,42,43). For example, the levofloxacin-procainamide interaction was suggested to be clinically important in patients who were "slow acetylators" (N-acetylation being an important metabolic step in procainamide elimination), as renal elimination of procainamide (rather than metabolism to N-acetylprocainamide) would become the primary excretion pathway for procainamide in such a scenario (16).…”

“…A significant decrease in renal clearance (CL ren ) and total clearance (CL tot ) (each ϳ13 to 28%) was observed, with an accompanying increase (ϳ28%) in the area under the concentration-time curve (AUC) from the zero time point to infinity (13)(14)(15). Similarly, patients coadministered ciprofloxacin, levofloxacin, or ofloxacin with procainamide, a class I antiarrhythmic agent and known inhibitor of the hOCTs, exhibited significantly reduced CL ren and increased AUC of procainamide and its metab-olite N-acetylprocainamide, suggesting potential renal hOCT inhibition by FQs (16)(17)(18)(19)(20)(21).…”

Inhibitory Interaction Potential of 22 Antituberculosis Drugs on Organic Anion and Cation Transporters of the SLC22A Family

“…The first-line anti-TB drug ethambutol showed a significant potential inhibition of OCT1-mediated uptake and possible drugdrug interactions (DDIs) but a negligible inhibitory effect on OCT2-mediated uptake (16). Procainamide, a substrate of OCTs, and N-acetylprocainamide renal clearance was decreased by coadministration of the fluoroquinolone derivatives levofloxacin and ciprofloxacin in healthy subjects, suggesting that a possible drug interaction took place during renal elimination (17).…”

Quinolones

“…This interaction was thus potentially more clinically-problematic with levofloxacin than with ciprofloxacin. In fact, of the ten volunteers, only one had a reduction in procainamide total body clearance exceeding 25% with ciprofloxacin while four had reductions in total body clearance of 30% or greater and three of the four had reductions in NAPA renal clearance of 30% or greater with levofloxacin [327].…”