Metabolism of Meloxicam in human liver involves cytochromes P4502C9 and 3A4

Abstract

1. The metabolism of Meloxicam (ME) and the cytochrome(s) P450 (CYPs) involved were analysed by using primary human hepatocytes, human liver microsomes and microsomes from recombinant human B-lymphoblastoid cell lines. 2. While human hepatocytes were capable of converting ME to a 5-hydroxymethyl metabolite (M7) and then to a 5-carboxyderivati ve (M5), human liver microsomes formed mostly only the 5-hydroxymethylde rivative. The kinetics of the formation of M7 by human liver microsomes were biphasic with K_m = 13.6 ± 9.5 and 381 ± 55.2 μM respectively. The corresponding V_max were 33.7 ± 24.2 and 143 ± 83.9 pmol/min/mg protein respectively. 3. CYP2C9 and, to a much lesser extent, CYP3A4 were found to convert ME to M7. The involvement of 2C9 was demonstrated by inhibition of tolbutamide hydroxylase activity in the presence of ME, inhibition of ME metabolism by sulphaphenazole, correlation between ME metabolism and tolbutamide hydroxylase activity and active metabolism of ME by recombinant2C9. The involvementof 3A4 was shown by inhibition of ME metabolism by ketoconazole, correlation between ME metabolism and nifedipine oxidase activity and metabolism of ME by recombinant 3A4. Kinetics of the formation of M7 by the individual enzymes resulted in a K_m = 9.6 μM and V_max = 8.4 pmol/min/mg protein for 2C9 and a K_m = 475 μM and V_max = 23 pmol/min/mg protein for 3A4.