IN-VITRO INTERACTION OF THE ANTIPSYCHOTIC AGENT OLANZAPINE WITH HUMANCYTOCHROMES P450 CYP2C9, CYP2C19, CYP2D6 AND CYP3A

1 The ability of olanzapine to inhibit the metabolism of marker cataly tic activities for the cytochromes P450 CYP3A, CYP2D6, CYP2C9, and CYP 2C19 was examined. This inhibitory capability was compared with that o btained with clozapine and known inhibitory compounds for the same cyt ochromes P450. 2 Olanzapine, clozapine, and ketoconazole were all foun d to non-competitively inhibit 1'-hydroxy midazolam formation, form se lective for CYP3A, yielding K-i values of 491, 99 and 0.11 mu M, respe ctively. The 1'-hydroxylation of bufuralol, form selective for CYP2D6, was competitively inhibited by olanzapine (K-i=89 mu M), clozapine (K -i=19 mu M), and quinidine (K-i=0.03 mu M). Tolbutamide metabolism to 4-hydroxy tolbutamide, form selective for CYP2C9, was competitively in hibited by clozapine and phenytoin (K-i of 31 mu M and 17 mu M, respec tively). Olanzapine non-competitively inhibited tolbutamide metabolism with a K-i of 715 mu M. The marker catalytic activity for CYP2C19 med iated metabolism, 4'-hydroxy S-mephenytoin formation, was competitivel y inhibited by clozapine (K-i=69 mu M) and omeprazole (K-i=4.1 mu M). Noncompetitive inhibition of CYP2C19 mediated metabolism was seen with olanzapine with a K-i of 920 mu M. 3 The calculated percent inhibitio n by olanzapine of substrates metabolized by CYP3A, CYP2D6, CYP2C9, an d CYP2C19 was modeled assuming a total plasma concentration in the the rapeutic range (0.2 mu M). Total olanzapine vs unbound olanzapine was used to model the worst case (most conservative) situation. In all cas es, the calculated percent inhibition of these cytochromes P450 by ola nzapine was <0.3%, suggesting that there would be little in vivo inhib ition of the metabolism of substrates of these enzymes when co-adminis tered with olanzapine.