Vol. 30, Issue 3, 301-306, March 2002

Phosphonate O-Deethylation of [4-(4-Bromo-2-Cyano-Phenylcarbamoyl) Benzyl]-Phosphonic Acid Diethyl Ester, a Lipoprotein Lipase-Promoting Agent, Catalyzed by Cytochrome P450 2C8 and 3A4 in Human Liver Microsomes

Yujiro Morioka, Makiko Otsu, Shinsaku Naito, and Teruko Imai

Naruto Research Institute, Otsuka Pharmaceutical Factory, Tokushima, Japan (Y.M., S.N.); and Faculty of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan (M.O., T.I.)

NO-1886 ([4-(4-bromo-2-cyano-phenylcarbamoyl) benzyl]-phosphonic acid diethyl ester) increases lipoprotein lipase activity, resulting in a reduction in plasma triglycerides and an increase in high-density lipoprotein cholesterol. The metabolism of NO-1886 in human liver was investigated in the present study. Ester cleavage of NO-1886 from diethyl phosphonate to monoethyl phosphonate was the major metabolic pathway catalyzed by cytochrome P450. In addition, the minor metabolic pathway in human liver was the hydrolysis of the amide bond of NO-1886 by a specific cytosolic esterase. Eadie-Hofstee plots of phosphonate O-deethylation of NO-1886 in human liver microsomes showed a biphasic curve, indicating low- and high-K_m components. Inhibition experiments with chemical inhibitors and antibodies against various cytochrome P450 isoforms suggested the involvement of CYP2C8 and CYP3A in the phosphonate O-deethylation. Recombinant CYP3A4 and CYP2C8 expressed in baculovirus-infected insect cells and human lymphoblastoid cells exhibited a high activity for phosphonate O-deethylation of NO-1886. The recombinant cytochrome P450 enzymes indicated that CYP2C8 and CYP3A4 were responsible for the low- and high-K_m components in human liver microsomes, respectively. The selectivity of CYP2C8 in catalyzing phosphonate O-deethylation indicates that coadministration of drugs that are metabolized by the same enzyme requires careful consideration.