Effect of concomitant administration of cimetidine and phenobarbital on antipyrine elimination and metabolite formation

Cimetidine 1000 mg/day and phenobarbital 100 mg/day were given to five healthy volunteers for 13 days in order to investigate the combined effect and time course of inhibition and induction on hepatic drug metabolism. The one-sample antipyrine saliva clearance (APC) and urinary metabolite profile were measured weekly, once before, two times during and four times after drug administration. On the second day of drug treatment APC was 0.7 fold and the formation clearance of the 3 oxidized metabolites 0.6 fold decreased owing to an early inhibition by cimetidine (p less than 0.05). After 8 days of concomitant drug administration, i.e. when the drug mediated inhibition and induction are supposed to be at maximum, mean APC was 0.85 times the initial value (p greater than 0.05), whereas the formation clearances of nor- and 3-hydroxymethylantipyrine were still significantly depressed. Four and 11 days after drug withdrawal, when phenobarbital, but not cimetidine could be demonstrated in plasma, APC was 1.2 times the initial value (p less than 0.05). The results suggest, that the respective effects of cimetidine and phenobarbital on antipyrine elimination are additive, when given concomitantly, but that cimetidine exerts a relatively greater inhibition in the phenobarbital induced state.