Effect of norfloxacin on theophylline metabolism

Abstract

The purpose of this study was to investigate the effect of norfloxacin on theophyiline elimination. Ten normal volunteers were studied. In a randomized crossover sequence, each subject received 6 mg of aminophyiline per kg of body weight by a 30-min intravenous infusion on day 4 of taking norfloxacin (400 mg every 12 h) or while drug free. Mean theophylline clearance decreased and mean elimination half-life increased after norfloxacin administration (from 0.036 ± 0.006 to 0.033 + 0.004 liter/h per kg and from 8.7 + 1.2 to 9.5 + 1.5 h, respectively; P < 0.05, Wilcoxon signed-ranks test). We conclude that norfloxacin taken in recommended doses for 3 days has a small inhibitory effect on theophylline metabolism that would probably not cause clinically important elevations in theophylline concentrations in most patients.Norfloxacin is a new quinolone antimicrobial agent recently approved for clinical use by the Food and Drug Administration. Coadministration of theophylline with three structurally related compounds, enoxacin, pefloxacin, and ciprofloxacin, has been reported to increase theophylline concentrations and cause toxicity (2,8,11,(13)(14)(15)(16); coadministration with nalidixic acid, another quinolone, does not (16). Ofloxacin has been reported to decrease or have no effect on theophylline clearance (3,5,16). It has been postulated that the 4-oxoquinolone metabolites rather than the parent drug cause the drug interaction (6, 16). Norfloxacin is metabolized to such a compound (17). We therefore sought to determine the effect of norfloxacin on theophylline pharmacokinetics.The purposes of this study were to (i) investigate the effect of norfloxacin on theophylline clearance and (ii) determine if any specific metabolic pathway is affected.MATERIALS AND METHODS Study population. Ten healthy, nonsmoking adults (four females and six males, ages 22 to 38) participated in the study, which was approved by the Human Research Review Committee at our institution. All subjects had normal results for physical examinations, urinalysis, and hematologic and biochemical studies. All subjects were within 10% of their ideal body weight (range, 54 to 89 kg).Drug administration. In a randomized, crossover sequence, subjects were administered 6 mg of aminophylline per kg of body weight by intravenous infusion over 30 min on day 4 of taking norfloxacin (400 mg every 12 h) or while drug free. The study periods were separated by 1 week. Subjects abstained from alcohol, foods known to induce drug metabolism, and other drugs for at least 72 h prior to receiving any study drug. Subjects also abstained from caffeine for at least 48 h prior to receiving aminophylline.Sample collection. Blood was taken from an indwelling cannula immediately before and 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 h after the aminophylline infusion. The blood was allowed to clot at room temperature, the samples were centrifuged at 800 x g, and the serum was collected. Urine was collected 0 to 24 h after aminophylline administration. * Correspondin...

Theophylline Toxicity Associated with the Administration of Ciprofloxacin in a Nursing Home Patient

“…It is interesting that this patient received two courses of norfloxacin without developing any clinically significant increase in theophylline levels. This is supportive of most studies of norfloxacin administration to healthy volunteers receiving aminophylline or theophylline, 7–10 although one study found an average decrease in theophylline clearance of 14.9%, 11 and Prince et al showed a decline in clearance of up to 31% compared to placebo among volunteers receiving an aminophylline infusion 12 . Three cases have been reported to the Food and Drug Administration suggestive of theophylline toxicity in patients taking norfloxacin 13 .…”

“…In patients with COPD, theophylline is commonly used to prevent bronchospasm, improve respiratory muscle function, and relieve dyspnea 6 . Several studies have examined the effect of quinolone administration on theophylline metabolism 4,5,7–15 . Raoof and colleagues administered ciprofloxacin at a dose of 750 mg twice daily to 33 hospitalized patients receiving theophylline.…”

Safety of fleroxacin coadministered with theophylline to young and elderly volunteers

“…Several mechanisms have been suggested to date to explain the influence that fluoroquinolones have on the pharmacokinetics of theophylline. Wijnands et al theorized that the 4-oxo-metabolite of fluoroquinolones such as enoxacin, ciprofloxacin, and pefloxacin acts as the inhibitor responsible for the interaction (33,34); however, good evidence against this supposition has recently been published (2,4,6).…”

“…perfusion over 30 min with a model 300 XL syringe-driver (Bard Medical Inc., Mississauga, Ontario, Canada). Blood samples were obtained at 0, 0.5, 1, 2, 3, 4,6,8,12,16,24, and 36 h, and urine was collected over the following intervals: 0, 0 to 2, 2 to 4, 4 to 8, 8 to 16, 16 to 24, and 24 to 36 h. Time-zero collection of urine allowed complete bladder emptying and a blank urine sample for analysis. Urine volume and pH were measured and recorded.…”

Absence of Effect of Rufloxacin on Theophylline Pharmacokinetics in Steady State

“…Yet, these agents are labeled for this interaction. The inhibitory effects were minor for norfloxacin (5,9,35,36) and neg-ligible or absent for ofloxacin (12,17,35,36,45), fleroxacin (38,40), lomefloxacin (32,46), temafloxacin (25,28,41), and sparfloxacin (21, 26) (for reviews on drug interactions between quinolones and methylxanthines, see references 13 and 43). The mechanism of this interaction is competitive inhibition of the enzyme mediating the main fraction of primary caffeine and theophylline metabolism (16), i.e., the cytochrome P-450 isoform CYP1A2 (15,18,49).…”