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.
Sarich
T C
TC
Department of Pharmacology & Therapeutics, Faculty of Medicine, University of British Columbia, Canada.
Wright
J M
JM
D000927:Anticonvulsants / Q000009:adverse effects* / Q000493:pharmacokinetics; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006801:Humans; D007037:Hypothyroidism / Q000097:blood / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008875:Middle Aged; D010672:Phenytoin / Q000009:adverse effects* / Q000493:pharmacokinetics; D013974:Thyroxine / Q000097:blood* / Q000378:metabolism
D000927:Anticonvulsants; D010672:Phenytoin; D013974:Thyroxine