Enoxacin Theophylline

Davis, J.D. Aarons, L. Houston, J.B. Relationship between enoxacin and ciprofloxacin plasma concentrations and theophylline disposition. Pharm.Res., 1994,11,1424-1428 [extracted enoxacin, theophylline plasma hydroxypropyltheophylline (IS) LOD 500 ng/mL]... 

The quinolones have been found to cause erosion of cartilage in the joints of immature animals [56]. This observation, which has been seen in several studies, has resulted in the contraindication of quinolones for the treatment of children. A study analyzing the risk-benefit situation for the use of pefloxacin in children (clinically, several adverse athralgic effects have been attributed to this agent) has appeared [57]. The underlying mechanism responsible for these effects has yet to be established, and the development of an agent which is safe for paediatric use would be a major advance in quinolone therapy. Some of the quinolones, such as enoxacin, have been shown to interfere with theophylline metabolism [58], and side-effects associated with this agent may be related to this property. 

Theophylline [P] Ciprofloxacin, enoxacin, and, to a lesser extent, norfloxacin inhibit theophylline metabolism gatifloxacin, levofloxacin, lomefloxacin, ofloxacin, and sparfloxacin appear to have little effect. 

The interaction between the quinolone antibacterials and CYP1A2 has been studied in some depth for enoxacin and pefloxacin. Both compounds have been shown to inhibit CYPlA2-mediated metabolism of caffeine in vitro (49). This in vitro inhibition translated into a twofold decrease in caffeine clearance by pefloxacin and a sixfold decrease in clearance by enoxacin (50). Because pefloxacin undergoes N-demethylation to norfloxacin (51) and norfloxacin is much more potent as an inhibitor than pefloxacin (50), the observed in vivo interaction seen for pefloxacin may, in part, be due to norfloxacin. Many other quinolone antibacterial agents have been investigated for their interaction with theophylline, and ciprofloxacin has also been shown to have notable inhibitory effects (52). 

Drug interactions The effect of antacids and cations on the absorption of these agents was considered above. Ciprofloxacin, ofloxacin and enoxacin can increase the serum levels of theophylline by inhibiting its metabolism. They also may raise levels of warfarin, caffeine and cyclosporine. Cimetidine interferes with the... 

The quinolones are contraindicated in patients with a history of hypersensitivity to any drug in this family. Absorption of the fluoroquinolones is reduced by antacids, iron, and zinc salts, and thus they should not be taken concurrently. Oral ciprofloxacin and enoxacin inhibit the metabolism of theophylline, and toxicity can occur when these two drugs are administered concurrently. Oral administration of the fluoroquinolones can cause convulsions and should therefore be done with caution in patients with central nervous system disorders. These drugs are not recommended for systemic administration in children, adolescents younger than age 18 years, or pregnant women. Topical administration is contraindicated for use in patients younger than 1 year of age. 

Fluoroquinolones. Ciprofloxacin and enoxacin (Pene-trex) may markedly increase serum concentrations of medications such as theophylline by inhibiting their hepatic metabolism. Certain other fluoroquinolones, such as levofloxacin (Levaquin), are not likely to inhibit hepatic enzyme systems and interact with these medications. 

Fluoroquinolones are potent inhibitors of hepatic cytochrome P450 isozymes (150). They inhibit theophylline metabolism, and accumulation of theophylline has led to seizures (151). Theophylline clearance is reduced by about 10% by norfloxacin, 30% by ciprofloxacin, and 70% by enoxacin (152-162). In a comparison of grepa-floxacin (400 and 600 mg/day) and ciprofloxacin, increased theophylline concentrations associated with clinical symptoms were found with both doses of grepa-floxacin but not in patients taking ciprofloxacin (17). The dosage of theophylline should be reduced when a quino-lone is given. 

Takagi K, Hasegawa T, Yamaki K, Suzuki R, Watanabe T, Satake T. Interaction between theophylline and enoxacin. Int J Clin Pharmacol Ther Toxicol 1988 26(6) 288-92. 

Beckmann J, Elsasser W, Gundert-Remy U, Hertrampf R. Enoxacin—a potent inhibitor of theophylline metabolism. Eur J Clin Pharmacol 1987 33(3) 227-30. 

Zhai, S. Korrapati, M.R. Wei, X. MuppaUa, S. Vestal, R.E. Simultaneous determination of theophylline, enoxacin and ciprofloxacin in human plasma and saliva hy high performance liquid chromatography. J. Chromatogr., Biomed. Appl. 1995, 669, 372-376. 

Some cytochrome P-450 isozymes, such as CYP lAl are inhibited by enoxacin, resulting in potentially important interactions with other drugs. For example, enoxacin has been reported to decrease theophylline clearance, causing increas plasma levels and increa.sed toxicity. Enoxacin forms insoluble chelates with divalent metal ions present in antacids and hcmalinic.s. which reduce its oral bioavailabilily. 

Rogge, M.C., Solomon, W.R., Sedman, A.J., Welling, P.G., Toothaker, R.D. Wagner, J.C. (1988) The theophylline-enoxacin interaction 1. Effect of enoxacin dose size on theophylline disposition. Clinical Pharmacology and Therapeutics, 44, 579-587. 

Fluoroquinolones are used in the treatment of purulent bronchitis and pneumonia and are hence likely to be administered concomitantly with theophylline. Drugs such as enoxacin and ciprofloxacin have been shown to reduce theophylline clearance by inhibiting metabolism. Lomefloxacin on the other hand has been shown to have no clinically significant effect on theophylline metabolism (40, 41). 

Noninterfering adenosine, albuterol, alphenal, aspirin, caffeine, carbamazepine, cefazo-lin, cephalexin, cephalothin, cimetidine, ciprofloxacin, claforan, desipramine, enoxacin, fleroxacin, furosemide, hydralazine, hydrochlorothiazide, minoxidil, norfloxacin, pheny-toin, propafenone, sulindac, teicoplanin, theophylline, vancomycin Interfering some indocyanine green impurities... 

Drugs of this class, especially those that undergo metabolism (e.g., norfloxacin, enoxacin and ciprofloxacin) can decrease the clearance of theophylline and significantly elevate plasma levels. 

CYP1A2 caffeine, imipramine, paracetamol, theophylline cigarette smoke, omeprazole cimetidine, ciprofloxacin, enoxacin, fluvoxamine... 

Enoxacin decreases theophylline Cl by 40-60%, peflocacin and ciprofloxacin by 30%.No effect was described for ofloxacin and norfloxacin. 

Theophylline serum levels can be markedly increased in most patients by enoxacin. Pipemidic acid and clinafloxacin probably interact similarly. Theophylline levels can also be markedly increased in some patients by ciprofloxacin, and possibly pe-floxacin. Norfloxacin, ofloxacin, pazufloxacin, or prulifloxacin normally cause a much smaller rise in theophylline levels. However, serious toxicity has been seen in few patients given norfloxacin. Fleroxacin, flumequine, gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, rufloxacin, spar-floxacin and trovafloxacin appear not to interact. 

Wijnands WJA, Vree TB, van Herwaarden CLA. Enoxacin decreases the clearance of theophylline in man. BrJ Clin Pharmacol (1985) 20, 583-8. 

Sorgel F, Mahr G, Granneman GR, Stephan U, Nickel P, Muth P. Effects of 2 quinolone antibacterials, temafloxacin and enoxacin, on theophylline pharmacokinetics. Clin PAarmacoAinef (1992) 22 (Su pl 1), 65-74. 

The interactions of enoxacin and ciprofloxacin with theophylline are well documented, well established and of clinical importance. The effect of enoxacin is marked and occurs in most patients, whereas the incidence with ciprofloxacin is uncertain and problems do not develop in all patients. The risk seems greatest in the elderly and those with theophylline levels already towards the top end of the therapeutic range. Toxicity may develop rapidly (within 2 to 3 days) unless the theophylline dosage is reduced. 

With enoxacin, it has been suggested that the dose of theophylline should be reduced by 50%, "" although reductions of 75% may possibly be necessary for those with high theophylline clearances. Alterations in the theophylline dose should be based on careful monitoring of theophylline levels. New steady-state serum theophylline levels are achieved within about 2 to 3 days of starting and stopping enoxacin. "... 

Direct information about clinafloxacin and pipemidic acid is more limited, but they also appear to cause a eonsiderable rise in serum theophylline levels, similar to enoxacin, and therefore it would seem prudent to anticipate the need for a dosage reduction and monitor theophylline levels close-... 

Koup JR, Toothaker RD, Posvar E, Sedman AJ, Colburn WA. Theophylline dosage adjustment during enoxacin coadm inistration. Antimicrob Agents Chemother (1990) 34, 803-7. 

Rogge MC, Solomon WR, Sedman AJ, Welling PG, Koi ) JR, Wagner JG. The theophylline-enoxacin interaction II. Changes in the disposition of theophylline and its metabolites during intermittent administration of enoxacin. Clin Pharmacol Ther( 9S9) 46, 420-8. 

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