Severe phenytoin intoxication in a subject homozygous for CYP2C9*3

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 (CY-P) enzymes responsible for phenytoin metabolism (CYP2C9 and CYP2C19) were suspected. Genotyping revealed that the patient was homozygous for the C gamma P2C9*3 allele (C gamma P2C9*3/*3) and heterozygous for the C gamma P2C19*2 allele (C gamma P2C19*1/*2). In view of the markedly reduced metabolic activity of C gamma P2C*3 in comparison with the wild-type enzyme (about one fifth) and of the minor role of C gamma P2C19 in phenytoin metabolism, it is likely that C gamma P2C9*3 mutation was largely responsible for drug overdose.