Analysis of parent drug-metabolite relationship in the presence of an inducer. Application to the carbamazepine-clobazam interaction in normal man.

An increase in drug metabolic clearance results in a decrease in concentration of parent drug but the effect on concentration of metabolite has been unclear. The effect of increases in the clearance of parent drug and/or metabolite upon the metabolite concentration, metabolite-to-parent drug concentration ratio, and fraction metabolized is described theoretically. It is shown that several combinations of increases in specific clearances can lead to qualitatively similar effects on steady state concentration of metabolite. The effect of increases in metabolic clearances of the clobazam-norclobazam system caused by carbamazepine treatment was studied in normal volunteers. The steady state concentration of metabolite (norclobazam) increased 1.4-fold and the ratio of metabolite to parent drug increased 4-fold. These effects of carbamazepine on clobazam-norclobazam pharmacokinetics could be a result of five theoretical cases. It is concluded that at least the formation clearance of norclobazam was increased. Carbamazepine treatment caused at least a 4-fold increase in the N-demethylation clearance of clobazam. It was also deduced that, in the baseline state, no more than 70% of the clobazam dose was metabolized to norclobazam, even though the norclobazam concentration was more than twice the clobazam concentration.