A PHARMACOKINETIC STUDY OF THE THEOPHYLLINE-ENOXACIN DRUG INTERACTION

Enoxacin is one of several quinolone-azaquinolone anti-infective agents currently being tested in man. Enoxacin is somewhat unique among the group of compounds in that it has an excellent pharmacokinetic profile and bactericidal spectrum. Enoxacin will likely become quite useful in the treatment of respiratory tract, bone and soft tissue infections.;The research objective of this dissertation was to pharmacokinetically characterize the theophylline-enoxacin drug interaction in humans. To accomplish this, sensitive and specific analytical methods were employed to quantitate theophylline and its three major metabolites as well as enoxacin and its oxo-metabolite in plasma and urine. The project was comprised of the analytical validation and two major human studies. The first human study determined the dependence of theophylline disposition on enoxacin dose size; the second human study characterized the onset and fall-off kinetics of theophylline and its metabolites upon commencement and cessation of enoxacin co-administration.;Indeed, enoxacin has a significant effect on the disposition of theophylline. In particular, the metabolism of theophylline is compromised along all three major metabolic pathways. This inhibition of oxidative metabolism appears saturable. Furthermore, it is unlikely that doses of enoxacin greater than those used in our study will cause greater decreases in theophylline clearance. Renal clearance of theophylline is unaffected by enoxacin. The interaction appears to be induced almost immediately upon the addition of enoxacin to the theophylline regimen. Recovery of normal theophylline pharmacokinetics appears to be just as rapid when enoxacin dosing ceased.;In spite of the adverse effect enoxacin has on theophylline elimination, enoxacin should not necessarily be excluded from the drug regimen of a patient who is concomitantly taking theophylline. A titrated reduction in the theophylline dose will insure that the patient remains free of theophylline toxicity while continuing to obtain its therapeutic benefit.;Over the past two years, however, some reports have been published that indicate enoxacin may adversely affect theophylline metabolism. As each new report appeared, it became more apparent that enoxacin was suppressing the elimination of theophylline to a significant degree. Considering that theophylline has a relatively narrow therapeutic range and that its side effects can be life-threatening, this interaction required a thorough investigation.