Diclofenac hepatotoxicity

Genetics Genetic differences in drug metabolising enzymes may predispose certain patients to hepatotoxicity. For example, the hlack and Hispanic population may he more prone to isoniazid toxicity Genetics may play a role in diclofenac hepatotoxicity... 

Deng X, Stachlewitz RE, Liguori MJ, Blomme EA, Waring IF, Luyendyk JP, Maddox JF, Ganey PE, Roth RA (2006) Modest inflammation enhances diclofenac hepatotoxicity in rats role of neutrophils and bacterial translocation. J Pharmacol Exp Ther 319 1191-1199 Deng X, Luyendyk JP, Zou W, Lu J, Malle E, Ganey PE, Roth RA (2007) Neutrophil interaction with the hemostatic system contributes to liver injury in rats cotreated with lipopolysaccharide and ranitidine. J Pharmacol Exp Ther 322 852-861... 

Aithal GP, Ramsay L, Daly AK, Soncbit N, Leathart JB, Alexander G, Kenna JG, Caldwell J, Day CP (2004) Hepatic adducts, drculating antibodies, and cytokine polymorphisms in patients with diclofenac hepatotoxicity. Hepatology 39 1430-1440... 

Minocycline is associated with a relatively high incidence of hepatotoxicity. In many cases it is quite distinct from minocycline-induced lupus, occurs earlier in the course of treatment (about 1 month), and the mechanism is unknown [62], However, in some cases the liver toxicity merges with the lupus-like syndrome, occurring after about a year of therapy, and is associated with ANA. This form is indistinguishable from idiopathic autoimmune hepatitis [63], and antibodies against Cyp 3A6 and Cyp 2C4 have been reported [64], Diclofenac has also been reported to cause hepatitis with autoimmune features such as ANA [65],... 

Such reactions can occur in other molecules containing aromatic amine functions without a para oxygen substituent. For instance diclofenac can be oxidized to a minor metabolite (5-OH) diclofenac which can be further oxidized [12] to the benzoqui-nine imine metabolite (Figure 8.10). Again, the reactivity of this intermediate has been implicated in the hepatotoxicity of the compound. 

Betulinic acid, an anticancer drug, the NS AID diclofenac and the cyclo-oxygenase 2 inhibitor nimesulide have all been shown to trigger MPT, leading to hepatotoxicity. 

Hepatotoxicity is an extremely rare but unpredictable side effect associated with most NSAIDs. There is some suggestion that diclofenac and sulindac have the highest risk, whereas ibuprofen has the lowest risk. 

Diclofenac may be a second-line option, but it has a higher risk of both hepatotoxicity and GI bleeding than ibuprofen. 

Hehgott SM, Sandberg-Cook J, Zakim D, Nestler J. Diclofenac-associated hepatotoxicity. JAMA 1990 264(20) 2660-2. 

Banks AT, Zimmerman HJ, Ishak KG, Harter JG. Diclofenac-associated hepatotoxicity analysis of 180 cases reported to the Food and Drug Administration as adverse reactions. Hepatology 1995 22(3) 820-7. 

C. P. (2007) Genetic susceptibility to diclofenac-induced hepatotoxicity contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterology, 132, 272-281. 

Some examples of bioactivation to hepatotoxic or IDR electrophilic intermediates are shown in Fig. 10.33. Bioactivation may occur by both oxidation and conjugation reactions, such as those with diclofenac, which undergoes the formation of an acyl glucuronide and/or acyl CoA (acylator intermediates) or to produce iminoquinones via formation of a phenol intermediator (Fig. 10.33-1) (92). The anticonvulsant carbamazepine is 2-hydroxylated and the elimination of the amide group yields the reactive quinoneimine intermediate (Fig. 10.33-2), and the antidepressant paroxetine and other xenobiotics with the common methylenedioxyphenyl nucleus undergo methylene oxidation to a... 

Schmitz, G. Lepper, H. Estler, C. J. Failure of calcium antagonistic agents to prevent hepatotoxicity induced by diclofenac. Pharmacol. Toxicol. 1995, 77, 32-35. 

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