Epilepsia, 48(3):490–496, 2007 Blackwell Publishing, Inc. C  2007 International League Against Epilepsy A Comparative Pharmacokinetic Study in Healthy Volunteers of the Effect of Carbamazepine and Oxcarbazepine on Cyp3a4 ∗ Astrid-Helene Andreasen, ∗ Kim Brøsen, and †Per Damkier ∗ Research Unit of Clinical Pharmacology, Institute of Public Health, University of Southern Denmark, Odense, Denmark, †Department of Biochemistry, Pharmacology & Genetics, Odense University Hospital, Odense, Denmark Summary: Purpose: Carbamazepine (CBZ) and oxcar- bazepine (OXCZ) are well-known inducers of drug metabolism via CYP3A4. Indirect interaction studies and clinical experience suggest that CBZ has a stronger potential in this regard than OXCZ. However this has never been subject to a direct comparative study. We performed a study in healthy volunteers to investigate the relative inductive effect of CBZ and OXCZ on CYP3A4 activity using the metabolism of quinidine as a biomarker reaction. Methods: Ten healthy, male volunteers participated in an open, randomized crossover study consisting of two periods separated by a 4-week wash-out period. The subjects received 1200 mg oral OXCZ daily for 17 days and 800 mg oral CBZ for 17 days. A single 200 mg oral dose of quinidine was ad- ministered at baseline and following administration of CBZ and OXCZ. Outcome parameters were the formation clearance of 3-hydroxyquinidine dose and the ratio of the AUCs of 3- hydroxyquinidine to quinidine. Results: Formation clearance of 3-hydroxyquinidine was in- creased by means of 89% (CI: 36–164; p = 0.0022) and 181% (CI: 120–260, p < 0.0001) after treatment with OXCZ and CBZ, respectively, compared to baseline. The relative inductive effect of CBZ was 46% higher than for OXCZ. AUC ratio increased by means of 161% (CI: 139–187, p < 0.0001) (OXCZ) and 222% (CI: 192–257, p < 0.0001) (CBZ). Quinidine Cmax decreased by means of 29% (CI: 16–40, p = 0.0018) (OXCZ) and 33% (CI: 18–45, p = 0.0020) (CBZ). T 1 2 decreased by means of 12% (CI: 6–17, p < 0.0014) (OXCZ) and 32% (CI: 25–38, p < 0.0001) (CBZ). t max was not changed in either period. Conclusion: We confirm a clinically significant inductive ef- fect of both OXCZ and CBZ. The inductive effect of CBZ was about 46% higher than that of OXCZ, a difference that may be of clinical relevance. Key Words: Carbamazepine— Oxcarbazepine—Drug–drug interaction—P450 induction— CYP3A4. Carbamazepine (CBZ) and oxcarbazepine (OXCZ) are two structurally similar and widely used antiepileptic drugs. Their clinical use in the treatment of epilepsy, espe- cially of CBZ, is complicated by a number of interactions mainly due to induction of drug metabolism, as reviewed by Patasalos (Patasalos and Perucca, 2003). In particular, CBZ induces the drug metabolizing enzyme cytochrome P450 3A4 (CYP3A4) (Spina et al., 1996). Additionally, CBZ has gained ground as an adjuvant drug in the treatment of certain psychiatric illnesses, par- ticularly affective disorders as mood-stabilizing clinical efficacy in the treatment of depression has been docu- mented (Stahl, 2004). A number of clinically significant Accepted August 7, 2006. Address correspondence and reprint requests to Per Damkier at De- partment of Biochemistry, Pharmacology & Genetics, Odense Uni- versity Hospital, DK-5000 Odense C, Denmark. E-mail: pdamkier@ health.sdu.dk doi: 10.1111/j.1528-1167.2007.00924.x interactions between CBZ and antidepressants and an- tipsychotics have been described, but systematic inter- action studies are available for only a very few of these potential interactions (Brosen and Krag-Sorensen, 1993; Lucas et al., 1998; Miceli et al., 2000; Sitsen et al., 2001; Szymura-Oleksiak et al., 2001; Pihlsgard and Eliasson, 2002). OXCZ, a prodrug that metabolizes to the active mono- hydroxy derivative 10-hydroxycarbazepine (Volosov et al., 1999), has to some extent replaced CBZ as an ad- juvant mood-stabilizer in psychiatry (Stahl, 2004). Clini- cal experience suggests that OXCZ to a lesser extent than CBZ is capable of inducing the metabolism of other drugs, and thus possesses a lower drug interaction potential. This is only sparsely and indirectly documented in lege artis clinical interaction studies, and no comparative study on this issue has been performed. Only a few methodolog- ically flawed studies with CYP3A4 substrates are avail- able. Area under the plasma concentration curve (AUC) of 490