Severe phenytoin intoxication in a subject homozygous for CYP2C9*3

Abstract

A 31-year-old woman who had a severe head injury was treated with oral phenytoin (100 mg 3 times a day) to prevent posttraumatic seizures. On day 10 of phenytoin treatment, 3 hours after the morning dose, the patient manifested neurologic signs compatible with phenytoin intoxication. Thus drug serum concentrations were monitored daily for 12 days. The elimination half-life was 103 hours, namely, about 5 times longer than the mean value generally quoted (22 hours). In the absence of any acquired predisposing factor for phenytoin toxicity, genetic mutations in the cytochrome P450 (CYP) enzymes responsible for phenytoin metabolism (CYP2C9 and CYP2C19) were suspected. Genotyping revealed that the patient was homozygous for the CYP2C9*3 allele (CYP2C9*3/*3) and heterozygous for the CYP2C19*2 allele (CYP2C19*1/*2). In view of the markedly reduced metabolic activity of CYP2C*3 in comparison with the wild-type enzyme (about one fifth) and of the minor role of CYP2C19 in phenytoin metabolism, it is likely that CYP2C9*3 mutation was largely responsible for drug overdose.