Time course of phenobarbital and cimetidine mediated changes in hepatic drug metabolism

Four healthy subjects were investigated weekly for 14 weeks by the antipyrine one sample saliva test, the 48-h urinary excretion of major antipyrine metabolites and the 2-h aminopyrine breath test before, during and after stimulation and inhibition of drug metabolism with phenobarbital and cimetidine, respectively. The phenobarbital-induced enhancement of antipyrine clearance (1.33-2.03 times) and of the aminopyrine breath test (0.94-1.19 times) occurred one week after beginning drug administration and persisted for 10 days after its cessation. The cimetidine-related inhibition of antipyrine clearance (0.62-0.85 times) and of the aminopyrine breath test (0.52-0.93 times) was observed 24 h after beginning cimetidine administration and subsided within two days after the last dose. During enhancement and inhibition the clearance of antipyrine to 3-hydroxymethyl-, 4-hydroxy- and norantipyrine varied as the total antipyrine clearance. The intraindividual variation in antipyrine clearance was 6-8%, and the corresponding variation in urinary excretion of antipyrine metabolites was 10-20%. It is concluded that the influence of phenobarbital and cimetidine on hepatic microsomal enzyme activity can be monitored simply by measurement of the blood concentration of the drug. Whether this simple relationship applies to other microsomally mediated drug interactions requires further evaluation.