1. The ability of olanzapine to inhibit the metabolism of marker catalytic activities for the cytochromes P450 CYP3A, CYP2D6, CYP2C9, and CYP2C19 was examined. This inhibitory capability was compared with that obtained with clozapine and known inhibitory compounds for the same cytochromes P450. 2. Olanzapine, clozapine, and ketoconazole were all found to non-competitively inhibit 1'-hydroxy midazolam formation, form selective for CYP3A, yielding Ki values of 491, 99 and 0.11 microM, respectively. The 1'-hydroxylation of bufuralol, form selective for CYP2D6, was competitively inhibited by olanzapine (Ki = 89 microM), clozapine (Ki = 19 microM), and quinidine (Ki = 0.03 microM). Tolbutamide metabolism to 4-hydroxy tolbutamide, form selective for CYP2C9, was competitively inhibited by clozapine and phenytoin (Ki of 31 microM and 17 microM, respectively). Olanzapine non-competitively inhibited tolbutamide metabolism with a Ki of 715 microM. The marker catalytic activity for CYP2C19 mediated metabolism, 4'-hydroxy S-mephenytoin formation, was competitively inhibited by clozapine (Ki = 69 microM) and omeprazole (Ki = 4.1 microM). Non-competitive inhibition of CYP2C19 mediated metabolism was seen with olanzapine with a Ki of 920 microM. 3. The calculated percent inhibition by olanzapine of substrates metabolized by CYP3A, CYP2D6, CYP2C9, and CYP2C19 was modeled assuming a total plasma concentration in the therapeutic range (0.2 microM). Total olanzapine vs unbound olanzapine was used to model the worst case (most conservative) situation. In all cases, the calculated percent inhibition of these cytochromes P450 by olanzapine was < 0.3%, suggesting that there would be little in vivo inhibition of the metabolism of substrates of these enzymes when co-administered with olanzapine.