AIMS: To identify the cytochrome P450 (CYP) isoform(s) responsible for the formation of the primary metabolite of ziprasidone (ziprasidone sulphoxide), to determine the kinetics of its formation and to predict possible drug interactions by investigating CYP isoform inhibition in an in vitro study. METHODS: In vitro metabolism of [14C]-ziprasidone was studied using human liver microsomes. The metabolites were identified using mass spectrometry. The kinetics of metabolite formation were determined using [14C]-ziprasidone (10-200 microM) over 5 min, and Km and Vmax were estimated from Lineweaver-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 Ki values were calculated. RESULTS: Three CYP-mediated metabolites - ziprasidone sulphoxide, ziprasidone sulphone and oxindole acetic acid - were identified. The apparent Km and Vmax values for the formation of the major metabolite, ziprasidone sulphoxide (measured as the sum of sulphoxide and sulphone) were 235 microM and 1.14 nmol mg(-1) protein min(-1), respectively. Isoform-selective inhibitors and recombinant enzymes indicated that CYP3A4 is responsible for the formation of ziprasidone metabolites. Ziprasidone was not a substrate for the other isoforms studied. Similar in vitro inhibition of CYP2D6 (Ki 6.9-16 microM) and CYP3A4 (Ki 64-80 microM) 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 Ki for either CYP2D6 inhibition or CYP3A4 inhibition. CONCLUSIONS: Ziprasidone is predominantly metabolized by CYP3A4 in human liver microsomes and is not expected to mediate drug interactions with coadministered CYP substrates, at clinically effective doses.
AIMS: To identify the cytochrome P450 (CYP) isoform(s) responsible for the formation of the primary metabolite of ziprasidone (ziprasidone sulphoxide), to determine the kinetics of its formation and to predict possible drug interactions by investigating CYP isoform inhibition in an in vitro study. METHODS: In vitro metabolism of [14C]-ziprasidone was studied using human liver microsomes. The metabolites were identified using mass spectrometry. The kinetics of metabolite formation were determined using [14C]-ziprasidone (10-200 microM) over 5 min, and Km and Vmax were estimated from Lineweaver-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 Ki values were calculated. RESULTS: Three CYP-mediated metabolites - ziprasidone sulphoxide, ziprasidone sulphone and oxindole acetic acid - were identified. The apparent Km and Vmax values for the formation of the major metabolite, ziprasidone sulphoxide (measured as the sum of sulphoxide and sulphone) were 235 microM and 1.14 nmol mg(-1) protein min(-1), respectively. Isoform-selective inhibitors and recombinant enzymes indicated that CYP3A4 is responsible for the formation of ziprasidone metabolites. Ziprasidone was not a substrate for the other isoforms studied. Similar in vitro inhibition of CYP2D6 (Ki 6.9-16 microM) and CYP3A4 (Ki 64-80 microM) 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 Ki for either CYP2D6 inhibition or CYP3A4 inhibition. CONCLUSIONS:Ziprasidone is predominantly metabolized by CYP3A4 in human liver microsomes and is not expected to mediate drug interactions with coadministered CYP substrates, at clinically effective doses.
Authors: D R Nelson; T Kamataki; D J Waxman; F P Guengerich; R W Estabrook; R Feyereisen; F J Gonzalez; M J Coon; I C Gunsalus; O Gotoh Journal: DNA Cell Biol Date: 1993 Jan-Feb Impact factor: 3.311
Authors: W Tassaneeyakul; D J Birkett; M E Veronese; M E McManus; R H Tukey; L C Quattrochi; H V Gelboin; J O Miners Journal: J Pharmacol Exp Ther Date: 1993-04 Impact factor: 4.030
Authors: P K Smith; R I Krohn; G T Hermanson; A K Mallia; F H Gartner; M D Provenzano; E K Fujimoto; N M Goeke; B J Olson; D C Klenk Journal: Anal Biochem Date: 1985-10 Impact factor: 3.365
Authors: G Everson; K C Lasseter; K E Anderson; L A Bauer; R L Carithens; K D Wilner; A Johnson; R J Anziano; T A Smolarek; R Z Turncliff Journal: Br J Clin Pharmacol Date: 2000 Impact factor: 4.335
Authors: F Aweeka; D Jayesekara; M Horton; S Swan; L Lambrecht; K D Wilner; J Sherwood; R J Anziano; T A Smolarek; R Z Turncliff Journal: Br J Clin Pharmacol Date: 2000 Impact factor: 4.335
Authors: Ádám Kiss; Ádám Menus; Katalin Tóth; Máté Déri; Dávid Sirok; Evelyn Gabri; Ales Belic; Gábor Csukly; István Bitter; Katalin Monostory Journal: Eur Arch Psychiatry Clin Neurosci Date: 2019-01-02 Impact factor: 5.270