Aceclofenac

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

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.

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Ana Estany GestalDegree in Pharmacy(USC)

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