Interaction of theophylline and ipriflavone at the cytochrome P450 level.

The effect of ipriflavone administered at a dose of 25 mg/kg and 100 mg/kg and coadministered with theophylline was investigated in selective assays of particular P450 isoenzyme activities. Significant changes could be detected in the activities of CYP2E1 and CYP3A in liver microsomes from male Wistar rats treated with ipriflavone. Induction of CYP2E1 was shown by aniline or p-nitro-phenol hydroxylation as a result of ipriflavone treatment. Aniline hydroxylation activity of CYP2E1 was induced by theophylline + ipriflavone (100 mg/kg) coadministration as well. It should be noted that theophylline does not cause alteration in CYP2E1 activity. On the other hand, ipriflavone inhibited ethylmorphine and aminopyrine N-demethylation activities catalysed by CYP3A. An additional effect in the inhibition of aminopyrine N-demethylation could be observed in microsomes from theophylline + ipriflavone treated groups. Our results suggest that the decrease in theophylline metabolism increasing level of serum theophylline of theophylline-treated patient during ipriflavone administration [Takahashi J. et al. (1992): Eur. J. Clin. Pharmacol., 43, 207-208] may be related to CYP3A inhibition by ipriflavone.