Diclofenac metabolism

Osorio-Lozada, A., Surapaneni, S., Skiles, G. and Subramanian, R. (2008) Biosynthesis of drug metabolites using microbes in hollow fiber cartridge reactors case study of diclofenac metabolism by Actinoplanes sp. Drug Metabolism and Disposition The Biological Fate of Chemicals, 36, 234-240. 

Tang W, Stearns RA, Kwei GY, et al. Interaction of diclofenac and quinidine in monkeys stimulation of diclofenac metabolism. J Pharmacol Exp Ther 1999 291 (3) 1068-1074. 

A second example of in vivo activation of drug metabolism was recently reported by Wei Tang and his associates (83). The in vitro addition of quinidine to monkey liver microsomes or hepatocytes stimulated the cytochrome P450 3A4-mediated metabolism of diclofenac to 5-hydroxydiclofenac (83). Although quinidine had little or no effect on the Km for diclofenac metabolism by monkey... 

Changes in partienlar residues of P450 2C9 yield markedly different effects depending on the substrate and reaction under consideration. For instance, the polymorphism 3 (1359 L), which appears to be very conservative, changed catalytic efficiencies of different reactions by factors of 3-to 27-fold (in vitro) [759]. Although the 2 and 3 polymorphisms cause considerable changes with some substrates, diclofenac metabolism is not altered [760], consistent with the in vitro findings. 

Di Marco, A., Marcucd, I., Chaudhary, A., Taliani, M. and Laufer, R. (2005) Development and validation of a high-throughput radiometric cyp2c9 inhibition assay using tritiated diclofenac. Drug Metabolism and Disposition, 33 (3), 359-364. 

Biodegradation occur either in aerobic or in anaerobic conditions, and as detailed below, it is the most important elimination process in WWTPs. This is an important degradation process for diclofenac, ofloxacin (OFLO), sulfamethoxazole and tetracyclines (TCs) [40]. Several fungi, such as Mucor ramannianus, present in soils, aheady have been shown to metabolize FQs [41]. 

Fig. 8.10 Scheme showing metabolism of diclofenac by oxidation (A) to benzoquinone imine (C) metabolites. 

Drugs that may be affected by HMG-CoA reductase inhibitors include oral contraceptives, diclofenac, digoxin, glyburide, phenytoin, and warfarin. Atorvastatin, lovastatin, and simvastatin are primarily metabolized by CYP3A4 they may interact with CYP3A4 inhibitors. 

D pharmacophore models for competitive inhibitors of CYP2C9 were built using Catalyst (173). Three different metabolic reactions, diclofenac 4 -hydroxylation, (S)-warfarin 7-hydroxylation, and tolbutamide 4-hydroxylation, were considered. The general characteristics of the three models were similar with distances between a hydrogen bond acceptor and a second hydrogen bond acceptor/donor being 3.4—5.7 A and the hydrophobic feature was positioned... 

Blot L, Marcelis A, Devogelaer JP, Manicourt DH. Effects of diclofenac, aceclofenac and meloxicam on the metabolism of proteoglycans and hyaluronan in osteoarthritic human cartilage. Br J Pharmacol. 2000 131 1413-1421. 

Tang W, Steams RA, Wang RW, et al. Roles of human hepatic cytochrome P450s 2C9 and 3A4 in the metabolic activation of diclofenac. Chem Res Toxicol 1999 12 192-199. 

Kumar S, Samuel K, Subramanian R, et al. Extrapolation of diclofenac clearance from in vitro microsomal metabolism data role of acyl glucuronidation and sequential oxidative metabolism of the acyl glucuronide. J Pharmacol Exp Ther 2002 303 969-978. 

Pmeksaritanont T, Li C, Tang C, et al. Rifampin induces the in vitro oxidative metabolism, but not the in vivo clearance of diclofenac in rhesus monkeys. Drug Metab Dispos 2006 34 1806-1810. 

In view of their incomplete oral bioavailability, several CYP2C substrates may undergo significant first-pass intestinal metabolism, including the CYP2C9 substrates verapamil (155), losartan (156), fluvastatin (157), and diclofenac (158), and the CYP2C19 substrates (5)-mephenytoin (159) and omeprazole... 

Shen S, Davis MR, Doss GA, et al. Metabolic activation of diclofenac by human cytochrome P4503A4 role of 5-hydroxydiclofenac. Chem Res Toxicol 1999 12 214—222. 

Fig. 16.6 Changes in bodyweight-normalized clearance (CL) with bodyweight for nine metabolized drugs (a) midazolam, intravenous, (b) midazolam (oral), (c) caffeine (oral), (d) diclofenac (IV),...

Idiosyncratic toxicity Metabolic abnormality No No Weeks-months Any Increased liver enzymes, hepatitis, jaundice Diclofenac Ketoconazole... 

Diclofenac 50 >99 1-2 <1 Negligible, if at all Extensive in liver - CYP2C9-hydroxylation then sulphation/ glucuronidation. First-pass metabolism of 50% 4- and possibly 3-hydroxydiclofenac but negligible antiinflammatory activity compared to diclofenac... 

Diclofenac undergoes presystemic metabolism, and administration via the rectal route will avoid this first-pass effect. This may be beneficial in patients who have significantly impaired metabolic capacity, where peak plasma levels may otherwise be raised if the oral route is used. 

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