Effect of mild therapeutic hypothermia on phenytoin pharmacokinetics

The authors examined the effect of mild therapeutic hypothermia on phenytoin pharmacokinetics in 14 patients with brain damage. Each patient was given phenytoin during and after mild therapeutic hypothermia. Plasma concentrations of total phenytoin, unbound phenytoin, and 5-(p-hydroxyphenyl)-5-phenylhydantoin (5-p-HPPH), the major metabolite of phenytoin, were measured. Pharmacokinetic parameters during and after mild therapeutic hypothermia were compared. Plasma concentrations of total and unbound phenytoin were significantly higher during hypothermia than after hypothermia. The area under the plasma concentration-time curve (zero to infinity) was increased by 180% and mean residence time was prolonged by 180% during hypothermia compared with the corresponding values after hypothermia. Moreover, the elimination constant (ke) was decreased by 50% and elimination clearance of phenytoin was decreased by 67% during hypothermia compared with the corresponding values after hypothermia. The plasma concentration of 5-p-HPPH was significantly lower during hypothermia than after hypothermia. These findings suggest that phenytoin metabolism is inhibited by mild therapeutic hypothermia.