A comparative pharmacokinetic study in healthy volunteers of the effect of carbamazepine and oxcarbazepine on cyp3a4.
OBJECTIVE
Carbamazepine (CBZ) and oxcarbazepine (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 administered 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 increased 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). T1/2 decreased by means of 12% (CI: 6-17, p<0.0014) (OXCZ) and 32% (CI: 25-38, p<0.0001) (CBZ). tmax was not changed in either period.


CONCLUSIONS
We confirm a clinically significant inductive effect 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.
Andreasen
Astrid-Helene
AH
Research Unit of Clinical Pharmacology, Institute of Public Health, University of Southern Denmark, Odense, Denmark.
Brøsen
Kim
K
Damkier
Per
P
D000284:Administration, Oral; D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D015415:Biomarkers; D002220:Carbamazepine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D008297:Male; D000078330:Oxcarbazepine; D011802:Quinidine / Q000031:analogs & derivatives / Q000378:metabolism
D000927:Anticonvulsants; D015415:Biomarkers; C013569:3-hydroxyquinidine; D002220:Carbamazepine; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D011802:Quinidine; D000078330:Oxcarbazepine