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Characterization of human cytochrome P450 enzymes involved in the in vitro metabolism of perospirone
Author(s) -
Kitamura Atsushi,
Mizuno Yoshiko,
Natsui Kiyoshi,
Yabuki Masashi,
Komuro Setsuko,
Kanamaru Hiroshi
Publication year - 2005
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.432
Subject(s) - ketoconazole , cyp3a4 , cyp2c8 , cytochrome p450 , quinidine , microsome , chemistry , metabolism , pharmacology , cyp2d6 , metabolite , cyp2c9 , biochemistry , in vitro , biology , antifungal , microbiology and biotechnology
In vitro studies were carried out to identify the major contribution of CYP2C8, CYP2D6 and CYP3A4 to the metabolism of perospirone (cis‐N‐[4‐[4‐(1,2‐benzisothiazol‐3‐yl)‐1‐piperazinyl]butyl]cyclohexane‐1,2‐dicarboximide monohydrochloride dehydrate), a novel antipsychotic agent, using human liver microsomes and expressed P450 isoforms. Quinidine (a specific inhibitor of CYP2D6) did not markedly affect the metabolism of perospirone, whereas quercetin (an inhibitor of CYP2C8) and ketoconazole (an inhibitor of CYP3A4) caused a decrease in the metabolism with human liver microsomes in a concentration dependent fashion. With 10 µ M quercetin, the metabolism of perospirone was inhibited by 60.0% and with 1 µ M ketoconazole almost complete inhibition was apparent. Anti‐CYP2C8 and anti‐CYP2D6 antisera did not exert marked effects, whereas anti‐CYP3A4 antiserum caused almost complete inhibition. With expressed P450s, K m and V max values were 1.09 µ M and 1.93 pmol/min/pmol P450 for CYP2C8, 1.38 µ M and 5.73 pmol/min/pmol P450 for CYP2D6, and 0.245 µ M and 61.3 pmol/min/pmol P450 for CYP3A4, respectively. These results indicated that the metabolism of perospirone in human liver was mainly catalysed by CYP3A4, and to a lesser extent CYP2C8 and CYP2D6 were responsible because kinetic data ( K m and V max ) of CYP2C8 and CYP2D6 suggested catalytic potential. Copyright © 2004 John Wiley & Sons, Ltd.