__(

Aceclofenac

26 de January de 2021

Monopgraph

Therapeutic action

Aceclofenac is a nonsteroidal anti-inflammatory drug used for the relief of inflammation and pain:- Low back pain.- Scapulohumeral periarthritis.- Extra-articular rheumatism.- Chronic osteoarthritis.- Rheumatoid arthritis.- Ankylosing spondylitis.

Further information

It is stimated that the CYP2C9 enzyme metabolizes 50% of aceclofenac. The remaining 50% ismetabolized through several enzymes pertaining to cytochrome P450. Furthermore, even though more than 30 variants in the coding region of the CYP2C9 gene have been described to date, only the variants CYP2C9*2 and CYP2C9*3 are frequent in the European population and have functional consequences on the CYP2C9 enzyme, therefore in the clinical practice the determination of these two variants should suffice.

Metabolism

Metabolismo del aceclofenaco
Metabolismo del aceclofenaco

After its oral administration, aceclofenac is rapidly and completely absorbed in the form of the intact parent drug. It is 99% bound to plasmatic proteins.It is metabolized to 4’-hydroxy-aceclofenac by means of the CYP2C9 enzyme, and to diclofenac through plasmatic sterases. por la enzima CYP2C9, y a diclofenaco a través de esterasas plasmáticas. 4’-hydroxy-aceclofenac is transformed to 4’-hydroxy-diclofenac also by action of plasmatic sterases. The metabolism of diclofenac implies several hydroxilation and acetyl-glucuronidation mecanisms. About 50% of diclofenaco is eliminated as 4’-hydroxy-diclofenac, a product of CYP2C9. The other metabolite in humans, 5-hydroxy-diclofenac seems to be the product of several enzymes including CYP2C8, CYP2C18, CYP2C19 and CYP2B6. It is believed that the enzyme CYP3A4 is also implicated, but its role has not been studied enough.The rest of the drug is metabolized by the UGT2B4 and UGT2B7 enzymes. The glucuronic conjugate of diclofenac is metabolized by CYP2C8.About two thirds of the administered dose is excreted in urine, mainly as hydroxy- metabolites.

Other factors to be considered

In general, NSAIDs should be used carefully when they are used toghether with other drugs that can increase the risk of ulceration, hemorrhage o renal dysfunction. Furthermore, the technical drug label of aceclofenac recommends that, to minimize adverse drug reactions, the lowest effective dose should be used for the shortest time possible in order to control the symptoms.

It is important to evaluate the dose of aceclofenac that it is administered, for two main reasons: (1) because the adverse gastrointestinal reactions of aceclofenac are dose-dependent and (2) because the presence of the CYP2C9*2 and specially the CYP2C9*3 variants, can lead to the synthesis of an enzyme with a lower metabolizing capacity compared with the wildtype enzyme. As a consequence, there would be a relative drug overdose increasing the risk for gastrointestinal hemorrhages. The therapeutic effect, however, has a ceiling.

Other adverse reactins have been described, but they are less frequent and are not dose-dependent, which include cardiovascular toxicity and hypersensitivity reactions. The cardiovascular damage has been described specially in patients with hypertension or kidney disorders which predispose them to suffer hydric retention.

Drugs that are substrate of CYP2C9, such as warfarin, phenytoin or other NSAIDs, should be used with precaution on patients taking celecoxib, because CYP2C9 is its main metabolic pathway and there can be competitive inhibition.Even though there are studies which propose studying other genes, encoding other enzymes that influence NSAIDs bioavailability (such as transporter proteins or the cycloxygenases themselves), to date there aren’t any association studies linking the presence of variants in those genes with an increased risk for adverse reactions in patients of European populations exposed to aceclofenac.

In practice several in vitro studies have shown that the presence of the variant CYP2C9*2 and specially CYP2C9*3, leads to the synthesis of an enzyme with a metabolizing capacity much lower than the wildtype, so patients who are carriers of these variants and take aceclofenac will suffer an overdose that might increase the risk for dose-dependent adverse reactions to aceclofenac, so it would be recommended to start the treatment with about 50% of the usual dose and evaluate the pharmacologic response and the possible adverse effects.

Conclusiones

Es importante tener en cuenta que más del 50% del aceclofenaco es metabolizado por la enzima CYP2C9. El consumo de dosis habituales de aceclofenaco por sujetos portadores de las variantesCYP2C9*2 y sobretodo de laCYP2C9*3, podría dar lugar a una sobredosis relativa que incrementaría el riesgo de sufrir hemorragias gastrointestinales, debido a la naturaleza dosis-dependiente de estas RAM.

Sin embargo, todavía es necesario realizar estudios que (1) cuantifiquen el incremento del riesgo de sufrir HGI en pacientes portadores de dichas variantes y expuestos a aceclofenaco, y (2), que determinen cuál es la dosis correcta para los pacientes con este perfil, para poder utilizarlo a posteriori en la práctica clínica diaria.

La determinación genética de las variantes codificantes del CYP2C9, podría disminuir la morbilidad gastrointestinal derivada del consumo de aceclofenaco, ya que podría evitarse la sobredosificación y, de esta forma, se minimizaría la aparición de las reacciones adversas dosis-dependientes.

Bibliography

  • Agúndez J et al (2009). Genetically based impairment in CYP2C8 and CYP2C9 dependent metabolism as a risk factor for gastrointestinal bleeding: Is a combination of pharmacogenomics and metabolomics required to improve personalized medicine? Expert Opin. Drug Metab. Toxicol; 5: 1-14.
  • Blanco G et al (2008). Interaction of CYP2C8 and CYP2C9 genotypes modifies the risk for nonsteroidal anti-inflammatory drugs-related acute gastrointestinal bleeding. Pharmacogenet Genomics; 18: 37-43.
  • Bort R et al (1996). Metabolism of aceclofenac in humans. Drug Metab Dispos; 24: 834-841.
  • Carbonell N et al (2010). CYP2C9*3 loss-of-function allele is associated with acute upper gastrointestinal bleeding related to the use of NSAIDs other than aspirin. Clinical Pharmacology and Therapeutics; 87: 693-698.
  • Crespi CL et al (1997). The R144C change in the CYP2C9*2 allele alters interaction of the cytochrome P450 with NADPH:cytochrome P450 oxidoreductase. Pharmacogenetics; 7: 203–1
  • Daily EB et al (2009). Cytochrome P450 2C8 pharmacogenetics. A review of clinical studies. Pharmacogenomics; 10: 1489-1510.
  • Haining RL et al (1996). Allelic variants of human cytochrome P450 2C9: baculovirus-mediated expression purification, structural characterization, substrate stereoselectivity and prochiral selectivity of the wild-type and I359L mutant forms. Arch Biochem Biophys; 333: 447–58.
  • Higashi MK et al (2002). Association between CYP2C9 genetic variants and coagulation-related outcomes during warfarin therapy. JAMA; 287: 1690-1698.
  • Laporte JR (2004). Upper gastrointestinal bleeding associated with the use of NSAIDs. Newer versus older agents. Drug Safety; 27: 411-420.
  • Martin JH et al (2001). Is cytochrome P450 2C9 genotype associated with NSAID ulceration? Br J Clin Pharmacol; 51: 627-630.
  • Musumba C et al (2009). Review article: cellular and molecular mechanisms of NSAID-induced peptic ulcers. Aliment Pharmacol Ther; 30: 517–531.
  • Pilotto A et al (2007). Genetic susceptibility to nonsteroidal anti-inflammatory drug-related gastroduodenal bleeding: role of cytochrome P450 2C9 polymorphisms. Gastroenterology; 133: 465-471.
  • Rettie AE et al (1994). Impaired S-warfarin metabolism catalyzed by R144C allelic variant of CYP2C9. Pharmacogenetics; 4: 39–42.
  • Sánchez-Diz P et al (2009). Prevalence of CYP2C9 polymorphisms in the south of Europe. Pharmacogenomics J; 9: 306-10.
  • Van Oijen et al (2006). Effect of a Specific Cyclooxygenase-Gene Polymorphism (A-842G/C50T) on the Occurrence of Peptic Ulcer Hemorrhage. Dig Dis Sci; DOI 10.1007/s10620-006-9475-8.
  • Vonkeman HE et al (2006). Allele variants of the cytochrome P450 2C9 genotype in white subjects from the Netherlands with serious gastroduodenal ulcers attributable to the use of NSAIDs. Clin Ther; 28: 1670-1676.

Ana Estany GestalDegree in Pharmacy(USC)

Last modified: Sep 6, 2017 @ 09:59 am

Do you want access to the full content? Purchase a paid plan and get full access to all our monographs.

Check out the plans