Activation of human cytochrome P-450 3A4-catalyzed meloxicam 5 '-methylhydroxylation by quinidine and hydroquinidine in vitro

In humans, meloxicam is metabolized mainly by cytochrome P-450 (CYP)-depend ent hydroxylation of the 5'-methyl group. The predominant P-450 enzyme invo lved in meloxicam metabolism is CYP 2C9, with a minor contribution of CYP 3 A4. Quinidine, a CYP 3A4 substrate commonly used as a selective in vitro in hibitor of CYP 2D6, was found to markedly increase the rate of meloxicam hy droxylation during in vitro experiments with human liver microsomes. A simi lar activation was observed with other compounds that are structurally rela ted to quinidine. Besides quinidine, quinine and hydroquinidine were the mo st potent activators of meloxicam hydroxylation. Using expressed cytochrome P-450 enzymes and selective chemical inhibitors of CYP 2C9 and CYP 3A4, it was found that quinidine markedly increased the rate of CYP 3A4-mediated m eloxicam hydroxylation but was virtually without effect on CYP 2C9. Kinetic analysis was performed to obtain insight into the possible mechanism of ac tivation of CYP 3A4 and into the mutual interaction of quinidine/hydroquini dine and meloxicam. Quinidine and hydroquinidine decreased K-m and increase d V-max of meloxicam hydroxylation, which was consistent with a mixed-type nonessential activation. Meloxicam, in turn, decreased both K-m and V-max o f quinidine metabolism by CYP 3A4, indicating an uncompetitive inhibition m echanism. These results support the assumption that CYP 3A4 possesses at le ast two different substrate-binding sites. A clinically relevant effect on meloxicam drug therapy is not expected, because the most likely outcome in practice is moderately decreased meloxicam plasma concentrations.