53467-23-5Relevant articles and documents
Diastereocontrol of nucleophilic attack of the rubanone carbonyl group via remote siloxy tether. Establishing the natural configuration at carbon C-3 of cinchona alkaloid
Langer, Peter,Hoffmann
, p. 9145 - 9158 (1997)
Cinchona alkaloid derivatives with natural configuration at C-3 have been constructed by Grignard reaction of protected rubanone 1-TBDS. The organomagnesium reagent attacks preferentially from the sterically more hindered endo face. Even L-Selectride reacts endo-selectively (9 : 1).
Activation of human cytochrome P-450 3A4-catalyzed meloxicam 5'- methylhydroxylation by quinidine and hydroquinidine in vitro
Ludwig, Eva,Schmid, Jochen,Beschke, Klaus,Ebner, Thomas
, p. 1 - 8 (2007/10/03)
In humans, meloxicam is metabolized mainly by cytochrome P-450 (CYP)- dependent hydroxylation of the 5'-methyl group. The predominant P-450 enzyme involved in meloxicam metabolism is CYP 2C9, with a minor contribution of CYP 3A4. Quinidine, a CYP 3A4 substrate commonly used as a selective in vitro inhibitor of CYP 2D6, was found to markedly increase the rate of meloxicam hydroxylation during in vitro experiments with human liver microsomes. A similar activation was observed with other compounds that are structurally related to quinidine. Besides quinidine, quinine and hydroquinidine were the most 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 meloxicam hydroxylation but was virtually without effect on CYP 2C9. Kinetic analysis was performed to obtain insight into the possible mechanism of activation of CYP 3A4 and into the mutual interaction of quinidine/hydroquinidine and meloxicam. Quinidine and hydroquinidine decreased K(m) and increased V(max) of meloxicam hydroxylation, which was consistent with a mixed-type nonessential activation. Meloxicam, in turn, decreased both K(m) and V(max) of quinidine metabolism by CYP 3A4, indicating an uncompetitive inhibition mechanism. These results support the assumption that CYP 3A4 possesses at least 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.
