Characterization of human cytochrome P450 enzymes involved in the in vitro metabolism of perospirone

• Published in: Biopharmaceutics & drug disposition 2005-03, Vol.26 (2), p.59-65
• Main Authors: Kitamura, Atsushi, Mizuno, Yoshiko, Natsui, Kiyoshi, Yabuki, Masashi, Komuro, Setsuko, Kanamaru, Hiroshi
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal - pharmacology; Antipsychotic Agents - chemistry; Antipsychotic Agents - metabolism; Antipsychotic Agents - pharmacokinetics; Biological and medical sciences; Carbon Radioisotopes; CYP2C8; CYP2D6; CYP3A4; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - immunology; Cytochrome P-450 Enzyme System - metabolism; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Female; Humans; in vitro metabolism; Indoles - chemistry; Indoles - metabolism; Indoles - pharmacokinetics; Isoenzymes - antagonists & inhibitors; Isoenzymes - immunology; Isoenzymes - metabolism; Isoindoles; Ketoconazole - pharmacology; Male; Medical sciences; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; Microsomes, Liver - metabolism; Models, Chemical; perospirone; Pharmacology. Drug treatments; Quercetin - pharmacology; Quinidine - pharmacology; Thiazoles - chemistry; Thiazoles - metabolism; Thiazoles - pharmacokinetics
• ISSN: 0142-2782; 1099-081X
• DOI: 10.1002/bdd.432

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 µM quercetin, the metabolism of perospirone was inhibited by 60.0% and with 1 µM 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, Km and Vmax values were 1.09 µM and 1.93 pmol/min/pmol P450 for CYP2C8, 1.38 µM and 5.73 pmol/min/pmol P450 for CYP2D6, and 0.245 µM 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 (Km and Vmax) of CYP2C8 and CYP2D6 suggested catalytic potential. Copyright © 2004 John Wiley & Sons, Ltd.