Pharmacogenetics of NSAIDs

There have been several studies exploring how genetic variability in pathways of relevance to NSAID metabolism and action may influence drug kinetics and/or the incidence of adverse effects. Recently, Kirchheiner et al. studied genetic variability of the cytochrome P450 (CYP) 2C9 enzyme and their influence on ibuprofen metabolism. CYP2C9 polymorphisms were identified, and subjects with various combinations of the *1, *2, *3 genotypes were studied. Metabolism of the dextrorotatory S-ibuprofen was significantly reduced in subjects carrying at least one *3 allele. In subjects homozygous for the *3 allele, S-ibuprofen clearance was reduced by approximately 50%. These subjects also displayed more significant inhibition of COX-1 and COX-2 (20). It has therefore been hypothesized that CYP2C9 genotypes may be associated with an increased risk of NSAID-associated adverse effects, such as upper GI haemorrhage. Although several other NSAIDs, including diclofenac and celecoxib, are also CYP2C9 substrates, studies suggest that the CYP2C9 genotype does not significantly affect the pharmacokinetics of either agent (21).

There is also a well-recognized risk of asthma being provoked or exacerbated in patients who use aspirin or NSAIDs. Approximately 10% to 11% of the asthmatics have been categorized as suffering from "aspirin-induced asthma" (22). The mechanism of worsening of asthma in this context appears to be mediated by alterations in eicosanoid metabolism. In particular, prostaglandin E2 (PGE2), produced by COX-1, acts to counterbalance proinflammatory leukotrienes especially cysteinyl leukotriene (Cys-LT). The addition of aspirin or other NSAIDs, which inhibit COX-1, results in rapid depletion of PGE2 and worsening of asthma and rhinitis symptoms. The enzyme, leukotriene C synthase (LTC4S) is upregulated in the bronchial mucosa of asthmatics. Patients with asthma who have an A-C transversion of nucleotide 444 in the LTC4S enzyme have increased expression of this enzyme in peripheral blood eosinophils. The C444 allele is also observed more commonly in patients with aspirin-induced asthma, compared with the healthy controls or asthmatics who are not aspirin-sensitive (23). For a full discussion of this topic see Chapter 6.

Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

Get My Free Ebook


Post a comment