Relative quantities of catalytically active CYP 2C9 and 2C19 in human liver microsomes: application of the relative activity factor approach

Journal of Pharmaceutical Sciences
K VenkatakrishnanD J Greenblatt

Abstract

The relative catalytic activities of CYP2C9 and CYP2C19 in human liver microsomes has been determined using the approach of relative activity factors (RAFs). Tolbutamide methylhydroxylation and S-mephenytoin 4'-hydroxylation were used as measures of CYP2C9 and CYP2C19 activity, respectively. The kinetics of these reactions were studied in human liver microsomes, in microsomes from human lymphoblastoid cells, and in insect cells expressing CYP2C9 and CYP2C19. RAFs were calculated as the ratio of Vmax (reaction velocity at saturating substrate concentrations) in human liver microsomes of the isoform-specific index reaction divided by the Vmax of the reaction catalyzed by the cDNA expressed isoform. RAFs were also determined for SUPERMIX, a commercially available mixture of cDNA expressed human drug metabolizing CYPs formulated to achieve a balance of enzyme activities similar to that found in human liver microsomes. Lymphoblast RAF2C9 in human liver microsomes ranged from 54 to 145 pmol CYP/mg protein (mean value: 87), while a value of 251 pmol CYP/mg protein was obtained for SUPERMIX. Insect cell RAF2C9 in human liver microsomes ranged from 1.6 to 143 pmol CYP/mg protein (mean value: 49), while a value of 201 pmol CYP/mg protein...Continue Reading

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Citations

Feb 28, 2001·Journal of Clinical Pharmacology·L L von MoltkeR I Shader
Nov 8, 2001·Journal of Clinical Pharmacology·K VenkatakrishnanD J Greenblatt
Mar 10, 2000·Clinical Pharmacokinetics·K VenkatakrishnanD J Greenblatt
Jun 12, 2009·Drug Metabolism Reviews·Shu-Feng ZhouBalram Chowbay
Jul 13, 2007·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Y MoonH S Lee
Aug 19, 2007·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·H S LeeS Y Kim
Feb 27, 2004·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·N J ProctorA Rostami-Hodjegan
Jul 13, 2013·Pharmaceutical Biology·Pius S FasinuBernd Rosenkranz
Mar 7, 2013·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·B WilliamsonM G Soars
Sep 3, 2016·Journal of Agricultural and Food Chemistry·Tingting GuoJian Kong
Jun 28, 2000·Biopharmaceutics & Drug Disposition·R I ShaderD J Greenblatt
Aug 3, 2004·The Journal of Pharmacy and Pharmacology·Lisa L von MoltkeDavid J Greenblatt
Mar 6, 2003·Biopharmaceutics & Drug Disposition·David J GreenblattDaniel A Garteiz
Dec 7, 2002·Biopharmaceutics & Drug Disposition·Lisa L von MoltkeDavid J Greenblatt
Dec 5, 2012·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Pius S FasinuBernd Rosenkranz
Jun 14, 2005·Clinical Chemistry·Landry K KamdemLeszek Wojnowski
Dec 10, 1999·Journal of Clinical Psychopharmacology·D J GreenblattR I Shader
Oct 3, 1999·Journal of Clinical Psychopharmacology·D J GreenblattR I Shader
Jun 26, 1999·British Journal of Clinical Pharmacology·L L Von MoltkeR I Shader
Jan 3, 2001·British Journal of Clinical Pharmacology·O V Olesen, K Linnet
Aug 8, 2006·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·C EmotoK Iwasaki
Aug 19, 2017·Expert Opinion on Drug Discovery·Li Di
Feb 18, 2006·The Journal of Nutrition·David J GreenblattLisa L von Moltke

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