Identification of the major human liver cytochrome P450 isoform(s) responsible for the formation of the primary metabolites of ziprasidone and prediction of possible drug interactions

Aims To identify the cytochrome P450 (CYP) isoform(s) responsible for the f ormation of the primary metabolite of ziprasidone (ziprasidone sulphoxide), to determine the kinetics of its formation and to predict possible drug in teractions by investigating CYP isoform inhibition in an in vitro study. Methods In vitro metabolism of [C-14]-ziprasidone was studied using human l iver microsomes. The metabolites were identified using mass spectrometry. T he kinetics of metabolite formation were determined using [C-14]-ziprasidon e (10-200 mu M) over 5 min, and k(m) and V-max were estimated from Lineweav er-Burk plots. IC50 values for the inhibition of specific probe substrates for CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, by ziprasidone, risperidone and 9-hydroxyrisperidone were also determined using human liver microsomes from three subjects. Mean K-i values were calculated. Results Three CYP-mediated metabolites - ziprasidone sulphoxide, ziprasidon e sulphone and oxindole acetic acid - were identified. The apparent K-m and V-max values for the formation of the major metabolite, ziprasidone sulpho xide (measured as the sum of sulphoxide and sulphone) were 235 mu M and 1.1 4 nmol mg(-1) protein min(-1) respectively. Isoform-selective inhibitors an d recombinant enzymes indicated that CYP3A4 is responsible for the formatio n of ziprasidone metabolites. Ziprasidone was not a substrate for the other isoforms studied. Similar in vitro inhibition of CYP2D6 (K-i 6.9-16 mu M) and CYP3A4 (K-i 64-80 mu M) was obtained with ziprasidone, risperidone and 9-hydroxyrisperidone. The in vivo free drug concentrations associated with clinically effective doses of ziprasidone are at least 1500-fold lower than the mean K-i for either CYP2D6 inhibition or CYP3A4 inhibition. Conclusions Ziprasidone is predominantly metabolized by CYP3A4 in human liv er microsomes and is not expected to mediate drug interactions with coadmin istered CYP substrates, at clinically effective doses.