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

• Published in: Drug metabolism and disposition Vol. 30; no. 3; pp. 301 - 306
• Main Authors: MORIOKA, Yujiro, OTSU, Makiko, NAITO, Shinsaku, IMAI, Teruko
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.03.2002
• Subjects: Aryl Hydrocarbon Hydroxylases; Benzamides - metabolism; Biological and medical sciences; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - metabolism; Dealkylation; General and cellular metabolism. Vitamins; Humans; Hypolipidemic Agents - metabolism; In Vitro Techniques; Lipoprotein Lipase - metabolism; Medical sciences; Microsomes, Liver - enzymology; Mixed Function Oxygenases - antagonists & inhibitors; Mixed Function Oxygenases - metabolism; Organophosphonates - metabolism; Organophosphorus Compounds - metabolism; Pharmacology. Drug treatments; Recombinant Proteins - metabolism; Steroid 16-alpha-Hydroxylase; Steroid Hydroxylases - antagonists & inhibitors; Steroid Hydroxylases - metabolism; Human; Enzyme; Digestive system; Toxicity; Cytochrome P450; Liver; Lipids; Esterases; Lipoprotein lipase; Microsome; Metabolism; Triglyceride; Carbamoyl; Cholesterol; Carboxylic ester hydrolases; Ester; Hydrolases; Lipoprotein HDL
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.30.3.301

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.