Influence of phenytoin on theophylline clearance

Abstract

The influence of phenytoin on theophylline elimination was studied in six healthy, nonsmoking subjects who were not taking any other drugs. Subjects were given an intravenous infusion of theophylline (aminophylline), 5 mg/kg, and several blood specimens were drawn over the following 24 hr for theophylline concentration determination. Subjects then began a 2-wk course on oral phenytoin, 300 mg/day, and on day 15 were again challenged with theophylline. For each subject theophylline clearance (ClT) was greater when taking phenytoin (range 31% to 65%). Mean ClT of the six subjects was 45% greater when taking phenytoin than when not taking phenytoin. In one subject, 24-hr urine collections were obtained in the untreated and treated state for analysis of theophylline metabolites. These results showed a general increase in excretion for each of the three major theophylline metabolites in the phenytoin pretreated state compared to the control state. Results indicate that phenytoin increases theophylline elimination. Patients taking phenytoin may require larger theophylline doses than recommended to achieve therapeutic blood theophylline concentrations.

Influence of Endogenous and Exogenous Effectors on the Pharmacokinetics of Theophylline

“…The simultaneous administration of this drug with theophylline leads to increased clearance of up to 56%. [263,265,266,284] It appears, that both isoenzymes of the cytochrome P450 cycle are equally involved. [265] An increase in clearance of between 25 and 91 % was also observed after administration of the tuberculostatic agent rifampicin (rifampin).…”

Aminophylline and CGS 8216 Reverse the Protective Action of Diazepam Against Electroconvulsions in Mice

“…Finally, whatever the nature of the antagonism by aminophylline of the anticonvulsant action of diazepam, our results strongly indicate that the methylxanthine should be used with caution and possibly avoided in epileptic patients. As a matter of fact, it has been recently suggested that aminophylline be administered in higher doses in patients taking phenytoin as an antiepileptic drug because of the latter-induced increase in the methylxanthine clearance (Miller et al, 1984). However, even at therapeutic antiasthmatic levels, aminophylline is likely to block adenosine receptors to a considerable degree, since theophylline at such levels produced 78% inhibition of the specific adenosine receptor ligand binding N6-cyclohexyladenosine (Weir et al, 1984).…”

Large Theophylline Requirements due to High Theophylline Clearance: Verification by the Antipyrine Test

“…The most likely explanation for the low plasma theophylline levels is induction o f its metabolism. This was probably due to his past history o f smok ing and chronic phenytoin use [10,[13][14][15][16], His history o f alcohol intake and steroid use may have also contributed.…”

“…The principal metabolites formed are 3-methyl xanthine, 1-methyluric acid and 1,3-dimethyluric acid, respectively [9], The ophylline clearance can be induced by a vari ety o f agents including rifampicin, cigarette smoke, benz[a]pyrene, charcoal, alcohol, phenytoin and sulfinpyrazone [1][2][3][10][11][12][13][14], Phénobarbital, however, has a relatively small influence on the clearance o f theophyl line [2].…”