In Vitro Assessment of 36 CYP 2 C 9 Allelic Isoforms Found in the C hinese Population on the Metabolism of Glimepiride

Of the 57 reported CYP 2 C 9 alleles, to date, 36 of them have been identified in the C hinese population. The aim of this study was to assess the catalytic characteristics of these allelic isoforms and their effects on the metabolism of glimepiride in vitro . Baculovirus‐mediated expressing system was used to highly express wild‐type and the 35 CYP 2 C 9 allelic variants in insect cell microsomes. Then, the enzymatic characteristics of each variant were evaluated using glimepiride as the substrate. Reactions were performed at 37°C with the insect microsomes and 0.125–10 μM glimepiride for 40 min. After termination, the products were extracted and used for signal collection by LC ‐ MS / MS . Of the 36 tested CYP 2 C 9 allelic isoforms, only four variants ( CYP 2 C 9.40, CYP 2 C 9.47, CYP 2 C 9.51 and CYP 2 C 9.54) exhibited similar relative clearance values to that of wild‐type CYP 2 C 9.1. In addition, one variant ( CYP 2 C 9.36) showed a higher intrinsic clearance value than the wild‐type protein, while the remaining 30 CYP 2 C 9 allelic isoforms exhibited significantly decreased clearance values (from 0.1% to 87.2%) compared to CYP 2 C 9.1. This study provided the most comprehensive data on the enzymatic activities of all reported CYP 2 C 9 variants in the C hinese population with regard to the commonly used antidiabetic drug, glimepiride. Our results indicate that most of the tested rare alleles significantly decrease the catalytic activity of CYP 2 C 9 variants towards glimepiride hydroxylation in vitro .