Objective: To study the effects of rifampicin, a potent inducer of the microsomal P₄₅₀ enzyme system and of specific isoforms of the uridine 5'-diphosphate(UDP)-glucuronyl- transferase enzyme system, and cimetidine, a known inhibitor of the hepatic microsomal cytochrome P₄₅₀ enzyme system, on pharmacokinetics and pharmacodynamics of lamotrigine in healthy subjects. Methods: Ten healthy male subjects received a single oral dose of 25 mg lamotrigine after a 5-day pretreatment with (1) cimetidine 800 mg divided into two equal doses, (2) rifampicin 600 mg, or (3) placebo. Serum and urine samples were analyzed using high-performance liquid chromatography. Changes in electroencephalographic (EEG) power were determined up to 48 h after lamotrigine administration. Results: The values of the pharmacokinetic parameters of lamotrigine were: Clearance over bioavailability (CL/F) 2.60 ± 0.40 l/h, renal clearance (CL(R)) 0.10 ± 0.03 l/h, terminal half-life (t( 1/2 )) 23.8 ± 2.1 h, mean peak serum concentration (C(max)) 0.29 ± 0.02 μg/l, time to reach C(max) (t(max)) 1.6 ± 0.28 h, and total area under the serum concentration-time curve (AUC(0-∞)) 703.99 ± 82.31 μg/ml/min (mean ± SEM). The amount of lamotrigine excreted as glucuronide was 8.90 ± 0.77 mg. Rifampicin significantly increased CL/F (5.13 ± 1.05 l/h) and the amount of lamotrigine excreted as glucuronide (12.12 ± 0.94 mg), whereas both t( 1/2 ) (14.1 ± 1.7 h) and AUC(0-∞) (396.24 ± 60.18 μg/ml/min) were decreased (P < 0.05). Cimetidine failed to affect pharmacokinetics of lamotrigine. Lamotrigine did not change EEG power. Conclusion: Rifampicin altered pharmacokinetics of lamotrigine due to induction of the hepatic enzymes responsible for glucuronidation, while coadministration of cimetidine to ongoing lamotrigine therapy has negligible effects on lamotrigine pharmacokinetics. Lamotrigine administered as a single dose of 25 mg has no effect on EEG power in healthy subjects.