Effects of chronic phenobarbital on verapamil disposition in humans

Very little is known about the effects of hepatic enzyme induction with phenobarbital on the disposition of high clearance drugs in humans. Our study was undertaken to investigate the effect of phenobarbital on both alpha-1 acid glycoprotein concentrations and total and free verapamil and its metabolites. Single oral, single i.v., and multiple oral verapamil administrations were evaluated before and after 21 days of phenobarbital treatment in healthy caucasian male volunteers. Significant changes in the pharmacokinetics of total and free verapamil and its metabolites occurred in a predictable manner. Mean total apparent oral clearance after a single dose of verapamil was increased after phenobarbital treatment (75.1 +/- 49.2 vs. 376.2 +/- 221.8 ml/min/kg, P less than .05). Clearance of free drug increased to a similar magnitude. Mean total verapamil systemic clearance was increased (9.95 +/- 1.3 vs. 18.9 +/- 8.7 ml/min/kg, P less than .05); however free drug clearance was not altered. After multiple oral administration, total verapamil apparent oral clearance was increased after phenobarbital pretreatment (21.2 +/- 9.8 vs. 91.2 +/- 28.5 ml/min/kg, P less than .05). Free drug clearance was increased similarly. Finally, the pharmacokinetic theories derived for hepatic extraction of drugs subject to a high metabolic clearance can be successfully applied to men after liver enzyme induction with phenobarbital.