Abstract
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.
Footnotes
-
Send reprint requests to: Shoji Kudo, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan. E-mail:s_kudo{at}research.otsuka.co.jp
- Abbreviations used are::
- OPC-13463
- methyl 2,6-dimethyl-4-(3-nitrophenyl)-3-carboxy-5-pyridinecarboxylate
- MOP-13031
- (±)-methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-carboxy-5-pyridine carboxylate
- CYP
- cytochrome P-450
- DMF
- N′,N′-dimethylformamide
- HPLC
- high-performance liquid chromatography
- Received June 15, 1998.
- Accepted September 27, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|