Ra. Lucas et al., A PHARMACOKINETIC INTERACTION BETWEEN CARBAMAZEPINE AND OLANZAPINE - OBSERVATIONS ON POSSIBLE MECHANISM, European Journal of Clinical Pharmacology, 54(8), 1998, pp. 639-643
Objective: Olanzapine is a novel antipsychotic, which is effective aga
inst both the positive and negative symptoms of schizophrenia and caus
es fewer extrapyramidal adverse effects than conventional antipsychoti
cs. The purpose of the present study was to assess the potential for a
pharmacokinetic interaction between olanzapine and carbamazepine, sin
ce these agents are likely to be used concomitantly in the treatment o
f manic psychotic disorder. Method: The pharmacokinetics of two single
therapeutic doses of olanzapine were determined in 11 healthy volunte
ers. The first dose of olanzapine (10 mg) was taken alone and the Seco
nd dose (10 mg) after 2 weeks of treatment with carbamazepine (200 mg
BID). Measurement of urinary 6 beta-hydroxycortisol/cortisol excretion
was used as an endogenous marker to confirm that induction of CYP3A4
by carbamazepine had occurred. Results: The dose of olanzapine given a
fter a 2-week pretreatment with carbamazepine was cleared more rapidly
than olanzapine given alone. Olanzapine pharmacokinetic values for C-
max and AUC were significantly lower after the second dose, the elimin
ation half-life was significantly shorter, and the clearance and volum
e of distribution were significantly increased. Conclusion: Carbamazep
ine has been shown to induce several P450 cytochromes including CYP3A4
and CYP1A2, Since CYP1A2 plays a role in the metabolic clearance of o
lanzapine, the interaction may be attributed to induction of CYP1A2 by
carbamazepine, leading to increased first-pass and systemic metabolis
m of olanzapine. The interaction is not considered to be of clinical s
ignificance because olanzapine has a wide therapeutic index, and the c
hanges in plasma concentration of olanzapine are within the fourfold v
ariation that occurs without concern for safety in a patient populatio
n.