Decreased capacity to metabolize diphenylhydantoin in a patient with hypersensitivity to warfarin

A 48 year old man with normal hepatic function presented with abnormally prolonged bleeding following orally administered warfarin. Warfarin and diphenylhydantoin are known to be hydroxylated in the liver. To investigate the possibility of the patient having a metabolic (hydroxylating) defect, his ability to metabolize diphenylhydantoin was studied, as it would have been unethical to administer warfarin again. Parallel studies were carried out on two healthy subjects as a basis for comparison. On three separate occasions the elimination half-life for diphenylhydantoin in the patient (158, 87, 72 hours) was significantly longer than those obtained in the normal subjects (31 and 32 hours). This difference was most probably due to decreased hydroxylation of diphenylhydantoin to 5-(p-hydroxy-phenyl)-5-phenylhydantoin since his urinary elimination of this substance was demonstrated to be significantly less than that of the normal subjects. The results suggest that this patient had a reduced capacity to hydroxylate diphenylhydantoin, and this defect in liver hydroxylation may explain his increased sensitivity to warfarin.