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 self-administer 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 min of the required time. Antibiotic therapy was continued until the last blood sample was obtained, and study phases were separated by at least 2 weeks.

On the day of procainamide administration, subjects were admitted at 0800 h to the Clinical Research Center for a 24-h stay. Subjects were required to fast, except for water, beginning at 2000 h the day before admission until 1200 h on the study day. Intravenous procainamide was administered over 3 h at a dose of 15 mg/kg of body weight. Blood samples (6 ml each) were obtained immediately before antiarrhythmic administration and at the following times after initiation of infusion: 1.5, 3, 3.3, 4, 5, 6, 8, 10, 12, 16, 24, and 48 h. Electrocardiogram, heart rate, and blood pressure measurements were also made at these times. Additionally, a complete urine collection was made for 24 h after procainamide administration.

After blood samples were allowed to clot, serum was separated and stored at −20°C until analyzed. After urine volume was measured, a 50-ml aliquot was saved and stored in an identical fashion. Procainamide and NAPA concentrations were measured by using a fluorescence polarization immunoassay (Abbott Diagnostics, Irving, Tex.) with interday coefficients of variation of <8% 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 <5% at 0.5, 5, and 50 mg/dl.

Procainamide and NAPA pharmacokinetic parameters were calculated by using model independent analysis (3). The pharmacodynamic response was determined by measuring the duration of QRS complexes and PR and QTc intervals on each electrocardiogram. Twenty-four-hour creatinine clearance (CrCl; in milliliters/minute) values were calculated by using measured serum and urine concentrations. Procainamide acetylator phenotype status was determined by taking the ratio of the NAPA and procainamide areas under the curve (AUCs) (slow acetylator, ≤0.8; rapid acetylator, ≥1.2) (13, 18). Statistical analysis was conducted by using repeated-measures analysis of variance, and a P value of <0.05 was considered statistically significant. If a significant difference was found, a comparison was made between control phase and treatment phase values by using the Tukey honestly significant difference test.

Treatment with levofloxacin caused changes in several pharmacokinetic parameters for procainamide (Table 1). Procainamide clearance decreased by 17% during concurrent levofloxacin treatment (range: 4 to 46%). Because the volume of distribution (V) was unchanged and clearance was decreased, procainamide half-life increased by 19% (range: 9 to 58%). Procainamide clearance changed due to a 26% reduction in procainamide renal clearance (range: 11 to 58%). The percentage of the procainamide dose excreted in the urine declined by 11% (range: 4 to 32%). The mechanism for the decrease in renal clearance appears to be decreased active tubular secretion, since the mean ratio of procainamide renal clearance to creatinine clearance declined from an average control value of 2.7 to 1.7 during levofloxacin treatment, a reduction of 29% (range: 14 to 60%).

TABLE 1.

Procainamide and NAPA pharmacokinetic parameters^a

Parameter	Result (mean ± SD) for:
	Control	Levofloxacin	Ciprofloxacin
PA Cl (liters/h/kg)	0.64 ± 0.13	0.53 ± 0.09**	0.59 ± 0.12
PA AUC (mg · h/liter)	23.4 ± 4.8	28.3 ± 4.8**	25.4 ± 5.2
PA renal Cl (liters/h/kg)	0.27 ± 0.09	0.20 ± 0.05***	0.23 ± 0.07*
PA nonrenal Cl (liters/h/kg)	0.37 ± 0.12	0.33 ± 0.08	0.36 ± 0.11
PA Varea (liters/kg)	2.5 ± 0.5	2.4 ± 0.4	2.5 ± 0.2
PA Vss (liters/kg)	2.5 ± 0.8	2.1 ± 0.3	2.5 ± 0.6
PA t1/2 (h)	2.7 ± 0.5	3.2 ± 1.2**	3.0 ± 0.6
PA furine (%)	42 ± 14	37 ± 9*	38 ± 12
NAPA renal Cl (liters/h/kg)	0.24 ± 0.10	0.19 ± 0.08**	0.21 ± 0.09
NAPA AUC (mg · h/liter)	13.6 ± 5.8	15.8 ± 7.4**	14.0 ± 6.9
NAPA furine (%)	25 ± 8	20 ± 5*	22 ± 6
PA renal Cl/CrCl	2.4 ± 0.8	1.7 ± 0.4***	2.1 ± 0.6
NAPA renal Cl/CrCl	2.1 ± 0.9	1.5 ± 0.7***	1.9 ± 0.8*
AUCNAPA/AUCPA	0.58 ± 0.72	0.56 ± 0.47	0.51 ± 0.41
Acetylator status	1 rapid/9 slow	NA	NA

^aPA, procainamide; f, fraction of dose; NA, not applicable; *, P < 0.05 compared to the control; **, P < 0.01 compared to the control; ***, P < 0.005 compared to the control.

Levofloxacin therapy caused similar changes in NAPA pharmacokinetic parameters. NAPA renal clearance declined by 21% (range: 4 to 38%), the percentage of procainamide dose excreted as NAPA decreased by 20% (range: 3 to 26%), and the ratio of NAPA renal clearance to creatinine clearance declined by 28% (range: 8 to 42%). As assessed by the AUC ratio for NAPA-to-procainamide concentrations, levofloxacin appeared to have similar effects on the renal handling of both drugs (control = 0.58, levofloxacin = 0.56; not significant).

Concurrent therapy with ciprofloxacin caused only minor changes in procainamide and NAPA pharmacokinetic parameters. During ciprofloxacin treatment, procainamide renal clearance decreased by 15% (range: 3 to 26%), and the ratio of NAPA renal clearance to creatinine clearance decreased by 10% (range: 2 to 21%).

Cotreatment with the fluoroquinolone antibiotics did not significantly change the pharmacodynamic parameters of electrocardiogram intervals, heart rate, or blood pressure compared to the control values.

When potential drug interactions are addressed in patient care settings, clinicians often fail to recognize that significant renal drug interactions occur. The organic anion transport (OAT) and organic cation transport (OCT) systems are two of the major families of renal drug transport systems in humans. Procainamide and NAPA are organic cations, are transported by OCT in the kidney, and undergo significant active secretion in the proximal tubule (7, 12, 17). Typically, the renal clearances of these two drugs are approximately two to three times the concurrent glomerular filtration rate in humans (4, 5, 18). Procainamide is a substrate for human OCT1, OCT2, and OCT3 transporters (12). The pattern of drug interactions with procainamide and NAPA are consistent with this mechanism of renal drug excretion. For example, both cimetidine and trimethoprim can cause clinically significant drug interactions with procainamide (4, 8, 10, 19, 20).

Interestingly, levofloxacin and ciprofloxacin are zwitterions, and so they potentially could be transported by either the OCT or the OAT system. Both undergo significant active secretion in the proximal renal tubule (14). At present, the transport systems involved in the renal disposition of these drugs are not completely understood. Levofloxacin has been reported to be a substrate for rat OCT2 and OAT-K2 (7). Renal drug transport of levofloxacin is inhibited by both cimetidine and tetraethylammonium, suggesting that OCT is involved in its elimination (21). Ciprofloxacin renal drug transport is inhibited by azlocillin and famotidine, implying that both the OAT and OCT systems are concerned with its elimination (1, 2).

Ofloxacin has been reported to interact with procainamide in humans, and so the potential for a drug interaction with levofloxacin exists (15). When nine healthy adults were administered ofloxacin (400 mg orally twice daily for five doses) and procainamide (1 g orally) was given, the average procainamide clearance decreased by 22% and the average procainamide renal clearance decreased by 30% compared to the control values. This finding is similar to the results of our investigation with levofloxacin, where procainamide clearance decreased by 17% and procainamide renal clearance declined by 26% compared to the control phase.

When assessing the clinical impact of our study, several things must be appreciated. First, the ranges of pharmacokinetic changes for procainamide and NAPA were large. Therefore, many patients who are given levofloxacin while taking procainamide will experience only minor changes in procainamide and NAPA serum concentrations. However, 4 of our 10 subjects had a 30% or greater change in procainamide clearance, and 3 of these 4 subjects also had a simultaneous 30% or greater change in NAPA renal clearance. There was a good correlation between decreases in the renal clearances of procainamide and NAPA during levofloxacin therapy (r = 0.79; P < 0.05). Patients with pharmacokinetic changes of this magnitude could have a clinically significant drug interaction, with the potential for concentration-related adverse drug reactions. Similarly, while most patients would not be expected to have a clinically significant drug interaction with ciprofloxacin while taking procainamide, one of the subjects had a decrease in procainamide clearance of more than 25% while taking concomitant therapy, which could potentially produce side effects. Second, 9 of our 10 subjects were slow acetylators, so renal clearance comprised a larger fraction of total clearance in these individuals. It is expected that the impact of reduced procainamide renal clearance would be lessened in rapid acetylators. Finally, although pharmacodynamic changes were not found during this investigation, only single doses of procainamide were used in the interest of subject safety. As a result, the maximum procainamide concentrations were in the lower end of the therapeutic range (∼4 to 6 mg/liter) and major changes in electrocardiographic intervals were not expected. In patients receiving chronic procainamide therapy with concentrations in the upper end of the therapeutic range (>10 mg/liter), it is possible that increases in PR intervals, QTc intervals, or QRS complexes could occur with the addition of levofloxacin therapy.

Patients taking levofloxacin with procainamide should be monitored for adverse drug reactions due to procainamide and NAPA accumulation. Procainamide and NAPA serum concentration monitoring and/or electrocardiogram monitoring should be considered if levofloxacin therapy is added for patients stabilized on procainamide therapy and if antiarrhythmic concentrations are at the high end of the therapeutic range.