Metabolic pathways for diclofenac
Biochemical Pharmacology , , Chemical Research in Toxicology , 22 12 , Acyl glucuronide metabolites: Implications for drug safety assessment. One possible reactive intermediate that would be expected to bind covalently to liver proteins was the p-benzoquinone imine derivative of 5-hydroxydiclofenac. Chemical Research in Toxicology , 25 11 , Kenny,, James L. Chemical Research in Toxicology , 21 5 , Lindon,, James L.
Hayes, Bernhard Hauer, Sabine L. Vermeulen, and Jan N.
Curr Drug Metab. Stachulski,, John R. Richter, Michele Tavanti, Nicholas J. Environmental Pollution. Turner, Martin A. Kevin Park, and, Andrew V. The reactive intermediates in this case were presumably diclofenac 1',4'- and 2,5-quinone imines, both of which were trapped by conjugation with glutathione and identified as glutathione adducts.
These cooperative interactions in recombinant systems, however, appeared to be influenced by enzyme host membranes of various cDNA-directed expressing CYP3A4. Hansen, Tommy N.
The 4'-hydroxylation of the drug appears to represent a feature reaction for CYP2C9 catalysis, and this regioselective oxidation is presumably dictated by interactions of the carboxylate moiety of the substrate with a putative cationic residue of the enzyme. Environmental Pollution. Chemical Research in Toxicology , 27 4 , Hrycay, Stelvio M. Toxicology in Vitro , 42, Clarke,, B. Chemical Research in Toxicology , 28 12 , Therapeutic use of diclofenac is associated with rare but sometimes fatal hepatotoxicity characterized by delayed onset of symptoms and lack of a clear dose-response relationship. It is conceivable that the acyl glucuronide and benzoquinone imines derived from diclofenac modify proteins covalently and thereby produce toxicity in susceptible patients via either direct disruption of critical cellular functions or elicitation of immunological responses. These results suggest that for appreciable Pmediated bioactivation of diclofenac to occur in vivo, an individual may have to have both high activities of P 3A4 and perhaps low activities of other enzymes that catalyze competing pathways of metabolism of diclofenac. The self-sufficient P RhF expressed in a whole cell system selectively catalyses the 5-hydroxylation of diclofenac. Diclofenac in Arabidopsis cells: Rapid formation of conjugates. Journal of Environmental Chemical Engineering , 6 2 , Copeland, and Zhiyang Zhao. These cooperative interactions in recombinant systems, however, appeared to be influenced by enzyme host membranes of various cDNA-directed expressing CYP3A4.
Therapeutic use of diclofenac is associated with rare but sometimes fatal hepatotoxicity characterized by delayed onset of symptoms and lack of a clear dose-response relationship.
Chemical Research in Toxicology22 12 Chemical Research in Toxicology32 1 Schenkman and James F.
Curr Drug Metab. In contrast, GSH did not prevent the covalent binding of diclofenac to human liver microsomes. Waldon, Yohannes Teffera, Adria E. These same glutathione adducts were detected in rats as well as in human hepatocytes treated with diclofenac, and a corresponding mercapturic acid derivative was identified in urine from patients administered the drug.
Chemical Research in Toxicology27 12 Biochemical Pharmacology,
based on 114 review