RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 303
OP 308
VO 27
IS 2
A1 Shoji Kudo
A1 Hiroshi Okumura
A1 Gohachiro Miyamoto
A1 Takashi Ishizaki
YR 1999
UL http://dmd.aspetjournals.org/content/27/2/303.abstract
AB 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