Hypothyroxinemia and phenytoin toxicity: a vicious circle.

Phenytoin is a widely used anticonvulsant which has a relatively narrow therapeutic range of serum concentrations, 40-80 mmol/l (10-20 mg/l). Phenytoin is known to show concentration-dependent kinetics within this therapeutic range. Because of this, small changes in dose and minor alterations in hepatic metabolism of phenytoin may cause a disproportionately large affect on serum concentrations. Hypothyroidism is associated with inhibition of hepatic oxidative metabolism of many drugs. However, there is a general consensus in the literature that serum phenytoin clearance is not influenced by thyroid functional status. This report describes a 63 year-old female who developed decreased serum free T4 (8 pmol/l) and phenytoin toxicity. We identified three other similar case reports. We propose that the following vicious circle may be involved in this interaction: induction by phenytoin of hepatic enzymes involved in the metabolism of T4 and T3, decreased serum free T4 levels causing decreased activity of hepatic NADPH cytochrome P-450 reductase, a resultant decrease in hepatic P-450 IIC9 catalyzed hydroxylation of phenytoin, increased serum phenytoin concentrations and further induction of T4 and T3 hepatic metabolism.