The antipsychotic clozapine is metabolized by the polymorphic human microsomal and recombinant cytochrome P450 2D6

A large interindividual variability for clozapine bioavailability and plasma steady-state concentrations and clearance exists. The enzymatic system which is involved in clozapine metabolism has not been fully characterized, yet structurally related tricyclic drugs have been found to be metabolized by cytochrome P450 2D6 (CYP2D6), which is polymorphically expressed in humans. The involvement of CYP2D6 in clozapine and fluperlapine metabolism was studied with human liver microsomes and in recombinant RT2D6 7-8 (RT2D6) cells, which specifically express human CYP2D6. Clozapine and its structural analog fluperlapine both bind to the active site of CYP2D6, as demonstrated by the competitive inhibition of dextromethorphan metabolism at inhibitor concentrations up to 40 microM. The inhibition constants (Ki) for both clozapine and fluperlapine were about 4 microM in microsomes from human liver. Clozapine exhibited a higher inhibition constant of 18.7 microM in microsomes from RT2D6 cells, but the difference was not statistically significant (P less than .05). These concentrations are close to the plasma concentrations of 0.3 to 3 microM achieved during clozapine therapy. Both clozapine and fluperlapine are also metabolized by CYP2D6. RT2D6 cells produced a number of metabolites from clozapine, whereas only a single metabolite was obtained from fluperlapine. The clozapine metabolites were not identified; however, they were different from N-oxide and N-demethyl clozapine. The fluperlapine metabolite was found to be the 7-hydroxy fluperlapine, which is also a major metabolite in vivo. In conclusion, both drug-drug interactions on the binding site of CYP2D6 and polymorphic metabolism of clozapine by CYP2D6 could contribute to the observed variability in clozapine kinetics in humans.(ABSTRACT TRUNCATED AT 250 WORDS)