COMMUNICATIONS

Time-Dependent Kinetics IV: Pharmacokinetic Theory of Enzyme Induction

A new microsampling technique is described and applied to the collection of a large number of blood samples from individual rats receiving a chronic intravenous antipyrine infusion. From these samples, a detailed description of the time-course of antipyrine autoinduction of clearance in the rat was provided. Antipyrine clearance was increased 4–5-fold over 8 d of antipyrine administration, with the increase in clearance following a monoexponential process in all animals. The assumption that the time-course of induction should reflect the degradation rate of induced enzymes was examined by comparing the half-life of antipyrine autoinduction with in vitro estimates for the half-life of induced cytochrome P-450 enzymes. The results of this comparison are discussed with respect to utilizing this kinetic model to quantitate the turnover of drug metabolism enzymes in vivo.

□ 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.

The intravenous pharmacokinetics of pentobarbital (30 mg/kg as pentobarbital sodium) in rats were studied at 0, 1, 2, 3, and 10 days after pretreatment with 0, 1, 5, 25, and 125 ppm of polychlorinated biphenyls in food. The polychlorinated biphenyls then were removed from the food, and the residual effects of the exposure on pentobarbital pharmacokinetics were studied at 15, 25, 45, and 70 days after initiation of the polychlorinated biphenyl exposure. The pharmacokinetics of pentobarbital were approximated to a one-compartment model. After pretreatment at 1 and 5 ppm for up to 10 days, all pentobarbital pharmacokinetic parameters obtained were comparable to control values. Pretreatment at 125 ppm significantly reduced the biological half-life and raised the total body elimination rate constant, total body clearance, and intrinsic clearance of pentobarbital after a 1-day exposure; all parameters apparently reached a new steady-state value by Days 5–10. Enhanced pentobarbital elimination at 25 ppm was observed after a 3-day exposure, but, again, the elimination parameters appeared to have reached a steady state after 5–10 days of pretreatment. Upon removal of the polychlorinated biphenyls, the various pharmacokinetic parameters showed a lag phase prior to a gradual return to control values. The study shows that intrinsic clearances rather than total body clearances or half-lives are more appropriate in assessing enzymatic induction in agents undergoing facile liver metabolic clearance that borders on blood flow rate dependency.

The applicability of a pharmacokinetic model for drug interactions by enzyme induction was tested in rhesus monkeys using a design in which both the inducer (carbamazepine) and the induced agent (clonazepam) were infused chronically. Two types of studies were conducted. Studies 1 and II examined the kinetic behavior of plasma clonazepam levels during induction and postinduction, respectively. The addition of carbamazepine (Study I) caused the preinduction clonazepam steady-state level to decrease exponentially to a lower (induced) steady state after lag times of 14.0–60.5 hr, and the removal of carbamazepine (Study II) caused induced clonazepam steady-state levels to climb exponentially to a higher steady state after lag times of 34.0–81.0 hr. The extent of induction ranged between 23 and 54%. The time course of clonazepam levels was described in terms of a one-compartment induction model with zero-order input and a metabolic clearance that increased (Study I) or decreased (Study II) exponentially with time. In both studies, induced clonazepam half-lives (3.7–7.7 hr) were significantly shorter (p < 0.0005) than control values (5.2–12.2 hr). Apparent enzyme turnover half-lives were shorter in Study II (2.7–19.3 hr) than in Study I (6.9–66.4 hr). A two- to threefold increase in urinary excretion of D-glucaric acid during carbamazepine administration provided additional evidence that the present interaction was due to enzyme induction.