Abstracts

Enzyme induction is a process by which either the quanity or activity of a cytochrome (CYP) enzyume is increased above its baseline. CYP induction results from an increase in gene transcription triggered by selected substances and drugs resulting in an increase in drug clearance and lower plasma concentrations. Once an enzyme inducer is started, it generally takes 2-4 weeks to reach the higher drug clearance although the time course of induction has not been well characterized. When an inducing drug is stopped, the effect is lost and drug clearance returns to baseline. This process is known as de-induction and the time course has been assumed to be the same as induction. However, there have been no studies which have looked at the time course and the effect of dose of the inducer on de-induction. The purpose of this project is to determine the time course and the dose at which the induction effect is lost., The antiepileptic drugs (AEDs) which are potent CYP 3A4/5 and uridine-diphosphate glucuronyl transferase (UGT) inducers include carbamazepine and phenytoin. LTG is a substrate for primarily for UGT. Patients selected for the study were on stable doses of one of the enzyme inducing AEDs (CBZ or PHT) and were also taking LTG. Patients were included who were to have the inducer discontinued and maintained on LTG monotherapy. Two trough plasma levels for the inducer and LTG were drawn before any changes in dose were made. Unit dose reduction was done biweekly (PHT 100 mg, CBZ 200 mg) and plasma samples were obtained biweekly during the taper. Plasma samples were collected three times a week for three weeks after the inducer was stopped and then weekly for three more weeks. Plasma concentrations were assayed using HPLC., Samples from 17 adult patients have been obtained. Mean LTG clearance (Cl) before dosage reduction of the EI-AEDs was 131 L. A linear reduction in LTG Cl was seen reaching 84.6 L the day the EI-AED was stopped. Further reduction in Cl occurred over the next three weeks reaching a mean of 48 L and plateaued at this level for the remainder of the study. Cl and change in Cl was similar across patients with the standard deviation ranging from 7.2 to 18.5 across the sampling times., 1. Approximately half of the de-induction occurs during the tapering of an EI-AEDs. The remaining induction effect is lost over the 3 weeks after the EI-AED is discontinued. Thus even a low dose of an EI-AED has a significant effect on the activity level of the glucuronidation pathway. The overall induction effect is a 2.5 fold increase in LTG clearance by EI-AEDs.,