TY - JOUR T1 - Cytochrome P-450 Isoforms Involved in Carboxylic Acid Ester Cleavage of Hantzsch Pyridine Ester of Pranidipine JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 303 LP - 308 VL - 27 IS - 2 AU - Shoji Kudo AU - Hiroshi Okumura AU - Gohachiro Miyamoto AU - Takashi Ishizaki Y1 - 1999/02/01 UR - http://dmd.aspetjournals.org/content/27/2/303.abstract N2 - Cytochrome P-450 (CYP) isoforms responsible for the cleavage of Hantzsch pyridine ester at the 3-position of pranidipine were studied in vitro using cDNA-expressed human CYP enzymes. CYP1A1, 1A2, 2D6, and 3A4 cleaved the ester with a catalytic activity of 5.5, 0.93, 13.1, and 22.4 nmol/30 min/nmol P-450, respectively. CYP2A6, 2B6, 2C8, 2C9, 2C19, and 2E1 were not involved in the de-esterification. TheKm and Vmaxvalues for the de-esterification were 11.8 μM and 0.47 nmol/min/nmol P-450 in the CYP2D6-catalyzed reaction and 8.7 μM and 0.84 nmol/min/nmol P-450 in the CYP3A4-catalyzed reaction. The intrinsic clearance (Vmax/Km) of the de-esterification by CYP3A4 was 2-fold greater than that by CYP2D6. Quinidine almost completely inhibited the CYP2D6-mediated de-esterification at the concentration of 1 × 10−6M. Ketoconazole and troleandomycin inhibited the CYP3A4-mediated reaction in a dose-related manner. The results indicate that although the multiple CYP isoforms can catalyze the de-esterification, CYP3A4 and 2D6 are the major isoforms. The American Society for Pharmacology and Experimental Therapeutics ER -