N-OXIDATION OF IRSOGLADINE BY THE CYP2C SUBFAMILY IN THE RAT, DOG, MONKEY AND MAN

1. The metabolism of irsogladine (ISG) was studied in hepatic microsom es from the rat, dog, monkey and man, and marked species differences w ere observed in N-oxidation of ISG. The rank order of the activity of the N-oxidation was shown to be man < monkey < dog < rat. 2. Anti-NADP H-P450 reductase antibody inhibited the formation of the N-oxidized me tabolite of ISG (ISG-N-oxide) in hepatic microsomes from rats by 74%. Anti-CYP2C11 antibody also inhibited the formation of ISG-N-oxide in h epatic microsomes from rat by 73 %, whereas anti-CYP2E1, 3A2 and 4A1 a ntibody did not inhibit N-oxidation. Thus, CYP2C11 in the rat is at le ast partially responsible for the N-oxidation of ISG in the rat. 3. An ti-CYP2C11 antibody also inhibited the formation of ISG-N-oxide in hep atic microsomes from the dog and monkey by 61 and 46 % respectively. T herefore, a isoform(s) similar to CYP2C11 partially contributed to the N-oxidation of ISG in the dog and monkey. In contrast, human CYP2C9, a member of the human CYP2C subfamily, did not catalyse the N-oxidatio n of ISG. 4. These findings show that the marked species difference in the N-oxidation of ISG is caused by the difference in the catalytic p roperties of CYP2C among the species examined.