Quinolones and Raised Plasma Concentrations of Theophylline

The influence of multiple doses of ofloxacin (ORF 18489) on the disposition of theophylline was studied in 15 male volunteers. Subjects were confined in the Clinical Research Unit for 13 days and given a xanthine-free diet. A single dose (3 mg/kg) of theophylline was given orally, and blood samples were collected at fixed time intervals for 36 h. The concentrations of theophylline were measured with TDX (Abbott Diagnostics, Irving, Tex.), and clearance was calculated. Theophylline clearance was used to individualize subsequent doses to achieve average steady-state theophylline concentrations in plasma of 10 mg/liter. Individualized theophylline doses were administered every 8 h until steady-state conditions were reached. Theophylline clearance was determined again at steady state and on days 7 and 8. On day 8, ofloxacin (400 mg every 12 h) was given concomitantly with theophylline. Theophylline clearance was measured again on day 12, after the last theophylline dose. Administration of ofloxacin for 1 day did not change theophylline clearance, but coadministration for 4 days significantly decreased theophylline clearance by 12.1% (P < 0.05). The area under the concentration-time curve for theophylline increased 9.9% (P < 0.05), and average steady-state concentrations in plasma increased 10.3% (P < 0.05). Despite changes in clearance, adverse effects of theophylline did not increase during coadministration of ofloxacin. Although statistically significant, the interaction between ofloxacin and theophylline is unlikely to be of major clinical importance.

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of theophylline clearance by coadministered ofloxacin without alteration of theophylline effects

Grégoire¹,

Grasela²,

Freer³

et al. 1987

“…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).…”

mentioning

confidence: 99%

Effect of norfloxacin on theophylline metabolism

Davis

Kelly

Quenzer

et al. 1989

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...

“…Enoxacin possesses the most potent metabolic inhibition, resulting in a 41 to 74% reduction in theophylline clearance (2,15,16). Patients receiving enoxacin and theophylline together without compensation for the interaction have suffered nausea, vomiting, seizures, hallucinations, and psychotic reactions (8). Clinically significant elevations in theophylline concentrations in serum associated with severe theophylline toxicity have also been reported with ciprofloxacin treatment (12).…”

mentioning

confidence: 99%

Effect of lomefloxacin on theophylline pharmacokinetics

Nix

Norman

Schentag

1989

A study involving 25 healthy male volunteers was conducted to evaluate the effect of lomefloxacin on the pharmacokinetics of theophylline. The mean age was 22.4 + 3.0 years, and the mean weight was 77.3 ± 7.7 kg. A single 6-mg/kg aminophylline dose was given intravenously on study days 1 and 15. The subjects received a 400-mg lomefloxacin dose (four 100-mg capsules) on study days 9 through 15. No treatment was given on study days 2 through 8. Thirteen blood samples were collected within 24 h after each aminophyUline dose. Theophylline concentrations in serum were measured by enzyme immunoassay (EMIT). The mean aminophylline dose was 437 + 36 mg, equivalent to 344 mg of theophylline. Multiple doses of lomefloxacin had no effect on the area under the concentration-time curve from 0 h to infinity, maximal concentration, or clearance of theophylline from serum. There was a slight increase in the theophylline half-life from 6.72 1.63 to 7.02 + 1.37 h after lomefloxacin dosing (P = 0.04); however, the change was clinically insignificant. No change in theophylline dose is required when lomefloxacin therapy is instituted in a patient receiving theophylline.Lomefloxacin is one of several new fluoroquinolone antimicrobial agents and is distinguished by a longer half-life (7.7 h), allowing once-daily dosing (9). Lomefloxacin possesses excellent in vitro activity against Haemophilus influenzae, Branhamella catarrhalis, Klebsiella pneumoniae, and several other organisms associated with purulent bronchitis and pneumonia in patients with obstructive lung disease (4). Thus, theophylline will likely be given with lomefloxacin in some patients.Other fluoroquinolones, including enoxacin and ciprofloxacin, may reduce theophylline clearance by inhibiting metabolism. Enoxacin possesses the most potent metabolic inhibition, resulting in a 41 to 74% reduction in theophylline clearance (2,15,16). Patients receiving enoxacin and theophylline together without compensation for the interaction have suffered nausea, vomiting, seizures, hallucinations, and psychotic reactions (8). Clinically significant elevations in theophylline concentrations in serum associated with severe theophylline toxicity have also been reported with ciprofloxacin treatment (12). Although ofloxacin was associated with a significant decline in theophylline clearance (12%), the magnitude was not clinically significant (6). This study was conducted to determine the effect of lomefloxacin on theophylline elimination. MATERIALS AND METHODSThe study was 0, 0.17, 0.33, 0.5, 0.75, 1, 2, 4, 8, 12, 16, 20, and 24 h relative to the beginning of each theophylline infusion. The blood samples were allowed to clot and were then centrifuged to separate the serum. The serum samples were maintained frozen at -20°C until the theophylline assay.Theophylline in human serum was determined by an enzyme immunoassay (EMIT; Syva Co., Palo Alto, Calif.). The assay precision ranged from 1.40 to 5.2%. The limit of sensitivity was 0.80 ,ug/ml. Concentrations below this value were reported as...