Characterization of human cytochrome P450 enzymes involved in the in vitro metabolism of perospirone.
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 microM quercetin, the metabolism of perospirone was inhibited by 60.0% and with 1 microM 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 microM and 1.93 pmol/min/pmol P450 for CYP2C8, 1.38 microM and 5.73 pmol/min/pmol P450 for CYP2D6, and 0.245 microM 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.
Kitamura
Atsushi
A
Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd, 1-98 Kasugade-naka 3-chome, Konohana-ku, Osaka 554-8588, Japan. kitamuraa@sc.sumitomo-chem.co.jp
Mizuno
Yoshiko
Y
Natsui
Kiyoshi
K
Yabuki
Masashi
M
Komuro
Setsuko
S
Kanamaru
Hiroshi
H
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D002250:Carbon Radioisotopes; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D054833:Isoindoles; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008956:Models, Chemical; D011794:Quercetin / Q000494:pharmacology; D011802:Quinidine / Q000494:pharmacology; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics
D000911:Antibodies, Monoclonal; D014150:Antipsychotic Agents; D002250:Carbon Radioisotopes; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007211:Indoles; D007527:Isoenzymes; D054833:Isoindoles; D013844:Thiazoles; D003577:Cytochrome P-450 Enzyme System; D011794:Quercetin; D011802:Quinidine; C065533:perospirone; D007654:Ketoconazole