RT Journal Article
SR Electronic
T1 Characterization of Human Cytochrome P450 Enzymes Involved in the Metabolism of Cilostazol
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1730
OP 1732
DO 10.1124/dmd.107.016758
VO 35
IS 10
A1 Hiratsuka, Masahiro
A1 Hinai, Yudai
A1 Sasaki, Takamitsu
A1 Konno, Yumiko
A1 Imagawa, Kenichi
A1 Ishikawa, Masaaki
A1 Mizugaki, Michinao
YR 2007
UL http://dmd.aspetjournals.org/content/35/10/1730.abstract
AB Cilostazol (OPC-13013; 6-[4-(1-cyclohexl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone) is widely used as an antiplatelet vasodilator agent. In vitro, the hydroxylation of the quinone moiety of cilostazol to OPC-13326 [6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-4-hydroxy-2(1H)-quinolinone], is the predominant route, and the hydroxylation of the hexane moiety to OPC-13217 is the second most predominant route. This study was carried out to identify and kinetically characterize the human cytochrome P450 (P450) isozymes responsible for the formation of the two major metabolites of cilostazol, namely, OPC-13326 and OPC-13217 [3,4-dihydro-6-[4-[1-(cis-4-hydroxycyclohexyl)-1H-tetrazol-5-yl)butoxy]-2(1H)-quinolinone)]. In in vitro studies using 14 recombinant human P450 isozymes, CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP2J2, CYP3A4, CYP3A5, and CYP4A11, cilostazol was metabolized to OPC-13326 mainly by CYP3A4 (Km = 5.26 μM, intrinsic clearance (CLint) = 0.34 μl/pmol P450/min), CYP1B1 (Km = 11.2 μM, CLint = 0.03 μl/pmol P450/min), and CYP3A5 (Km = 2.89 μM, CLint = 0.05 μl/pmol P450/min) and to OPC-13217 mainly by CYP3A5 (Km = 1.60 μM, CLint = 0.57 μl/pmol P450/min), CYP2C19 (Km = 5.95 μM, CLint = 0.16 μl/pmol P450/min), CYP3A4 (Km = 5.35 μM, CLint = 0.10 μl/pmol P450/min), and CYP2C8 (Km = 33.8 μM, CLint = 0.009 μl/pmol P450/min). The present study showed that the two major metabolites of cilostazol in vitro, namely, OPC-13326 and OPC-13217, are mainly catalyzed by CYP3A4 and CYP3A5, respectively. The American Society for Pharmacology and Experimental Therapeutics