Angiotensin II Receptor Blockers Inhibit the Generation of Epoxyeicosatrienoic Acid from Arachidonic Acid in Recombinant CYP2C9, CYP2J2 and Human Liver Microsomes

• Published in: Basic & clinical pharmacology & toxicology Vol. 121; no. 4; pp. 239 - 245
• Main Authors: Senda, Asuna, Mukai, Yuji, Hayakawa, Toru, Kato, Yuka, Eliasson, Erik, Rane, Anders, Toda, Takaki, Inotsume, Nobuo
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.10.2017
• Subjects: 8,11,14-Eicosatrienoic Acid - analogs & derivatives; 8,11,14-Eicosatrienoic Acid - metabolism; Angiotensin; Angiotensin II; Angiotensin II Type 1 Receptor Blockers - adverse effects; Angiotensin II Type 1 Receptor Blockers - pharmacology; Arachidonic acid; Arachidonic Acid - metabolism; Cytochrome P-450 CYP2C9 - metabolism; Cytochrome P-450 CYP2C9 Inhibitors - adverse effects; Cytochrome P-450 CYP2C9 Inhibitors - pharmacology; Cytochrome P-450 Enzyme System - metabolism; Cytochrome P450; Cytochromes P450; Dose-Response Relationship, Drug; Drug Interactions; Enzymes; Humans; Kinetics; Liver; Liver - drug effects; Liver - enzymology; Medicin och hälsovetenskap; Metabolism; Microsomes; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; Recombinant Proteins - metabolism; Vasodilation
• ISSN: 1742-7835; 1742-7843; 1742-7843
• DOI: 10.1111/bcpt.12789

Cytochrome P450 (CYP) 2C9, CYP2C8 and CYP2J2 enzymes, which metabolize arachidonic acid (AA) to epoxyeicosatrienoic acids, have cardioprotective effects including anti‐inflammation and vasodilation. We have recently shown that some angiotensin II receptor blockers (ARBs) may inhibit AA metabolism via CYP2C8. Using recombinant CYP2C9, CYP2J2 and human liver microsomes (HLMs), the aim was now to compare the ability of six different clinically used ARBs to inhibit AA metabolism in vitro. The rank order of the ARBs for the 50% inhibitory concentration (IC50) of AA metabolism was losartan <telmisartan <irbesartan <candesartan <olmesartan <valsartan via CYP2C9, and telmisartan <irbesartan <olmesartan <losartan <candesartan and valsartan via CYP2J2. The order for the HLMs was losartan <telmisartan <irbesartan <olmesartan <candesartan <valsartan. Some ARBs having lower concentration of IC50 indicate that these ARBs might inhibit the AA metabolism in the liver.