METABOLISM OF MELOXICAM IN HUMAN LIVER INVOLVES CYTOCHROMES P4502C9 AND 3A4

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 cel l lines. 2. While human hepatocytes were capable of converting ME to a 5-hydroxymethyl metabolite (M7) and then to a 5-carboxyderivative (M5 ), human liver microsomes formed mostly only the 5-hydroxymethylderiva tive. The kinetics of the formation of M7 by human liver microsomes we re biphasic with K-m = 13.6 +/- 9.5 and 381 +/- 55.2 mu M respectively . The corresponding V-max were 33.7 +/- 24.2 and 14.3 +/- 83.9 pmol/mi n/mg protein respectively. 3. CYP2C9 and, to a much lesser extent, CYP 3A4 were found to convert ME to M7. The involvement of 2C9 was demonst rated by inhibition of tolbutamide hydroxylase activity in the presenc e of ME, inhibition of ME metabolism by sulphaphenazole, correlation b etween ME metabolism and tolbutamide hydroxylase activity and active m etabolism of ME by recombinant 2C9. The involvement of 3A4 was shown b y inhibition of ME metabolism by ketoconazole, correlation between ME metabolism and nifedipine oxidase activity and metabolism of ME by rec ombinant 3A4. Kinetics of the formation of M7 by the individual enzyme s resulted in a K-m = 9.6 mu m and V-max = 8.4 pmol/min/mg protein for 2C9 and a K-m = 475 mu M and V-max = 23 pmol/min/mg protein for 3A4.