Time-dependent kinetics VII: effect of diurnal oscillations on the time course of carbamazepine autoinduction in the rhesus monkey.

Extensive blood sampling and repeated long-term carbamazepine infusions were carried out in four rhesus monkeys to examine the time course of carbamazepine autoinduction in detail and assess the intraanimal variability in the rate constant of induction. Diurnal oscillations in carbamazepine blood levels were observed during all infusions and these prevented a good data fit for the biochemical model previously proposed for describing the decline in drug blood levels during induction by carbamazepine. An attempt at fitting only selected blood samples to the model resulted in variable (and perhaps questionable) induction rate constants, even in the same animal. Previous variability in calculated induction rate constants may be due to the presence of diurnal oscillations superimposed on the autoinduction phenomenon. It is proposed that the simultaneous expression of diurnal oscillations and autoinduction are the result of effects on drug metabolism at two independent levels.