We recently observed a patient in whom we suspected an interaction of azapropazone with phenytoin resulting in phenytoin toxicity. This and a report of a similar case' led us to investigate the effect of azapropazone on steady-state plasma phenytoin concentrations in five healthy volunteers. Subjects and results INITIAL CASEA 60-year-old man who had had grand mal epilepsy for three years was receiving maintenance treatment of phenytoin 300 mg daily. He was given azapropazone 600 mg twice daily for arthralgia and two weeks later developed increasing confusion, nausea, diplopia, and vertigo. Examination showed nystagmus on lateral gaze. Plasma phenytoin concentration was 148 Hmol/l (37 isg/ml). Phenytoin and azapropazone were stopped, and his condition returned to normal within a week. Phenytoin 300 mg daily was restarted without recurrence of toxicity. Two months later his plasma phenytoin concentration was 32 ,umolll (8 tLg/ml). rose to 27 JLmol/l (6&7 itg/ml) and then fell to 10 jLmol/l (2-5 jLg/ml). CommentAzapropazone added during steady-state administration of phenytoin doubled plasma phenytoin concentrations. The initial fall in phenytoin concentrations when azapropazone was added, followed by a gradual rise, resembled the results of Neuvonen et al,3 who observed similar changes in epileptic patients starting phenylbutazone, a pyrazolidine derivative related to azapropazone. Phenytoin is 90% and azapropazone 95% plasma protein bound, and probably azapropazone displaces phenytoin from protein-binding sites, leading to an increase in the free fraction of phenytoin in the plasma and an increase in the rate of clearance of total phenytoin with a decrease in plasma total phenytoin concentration. The reverse would happen on withdrawal of azapropazone (see figure).The subsequent rise in plasma phenytoin concentrations was probably due to decreased clearance of phenytoin. Metabolism of phenytoin is the main mechanism of clearance of the drug, and there is good evidence that some drugs-for example, chloramphenicol and isoniazid-inhibit metabolism of phenytoin.4 Azapropazone decreases the rate of clearance, and therefore presumably inhibits the metabolism, of tolbutamide.5 An effect on absorption of phenytoin is unlikely since phenytoin (Epanutin) is almost completely absorbed. We cannot rule out altered tissue distribution occurring during this interaction, but that alone would not account for the changes in steady-state plasma phenytoin concentrations during azapropazone treatment.We used doses of phenytoin that produced initial plasma phenytoin concentrations well below the therapeutic range (40-80 ,umol/l; 10-20 pg/ml). The concentrations doubled during azapropazone treatment, and even greater changes might be expected in patients starting with concentrations within the therapeutic range because of the non-linearity of phenytoin pharmacokinetics. This is therefore a potentially dangerous interaction. We advise avoiding azapropazone in patients treated with phenytoin.The Committee
We have investigated the interaction of azapropazone with phenytoin in five healthy volunteers. From steady‐state plasma phenytoin concentrations of about 17 mumol/l there was at least a two‐fold increase following the introduction of azapropazone. The main mechanism of the interaction was a decrease in phenytoin clearance, attributable to competitive inhibition by azapropazone of phenytoin p‐hydroxylation. Protein‐binding of phenytoin in the plasma (as assessed by salivary phenytoin concentrations) was significantly reduced from 92 to 90% by azapropazone and similar changes occurred in in vitro studies of [3H]‐ phenytoin protein binding.
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