Pharmacogenetics of anti-leukotriene drugs

Cysteinyl leukotrienes, a group of compounds with potent bioactivity to constrict bronchial smooth muscle cells and recruit eosinophils and other inflammatory cells into the airways, act as key modulators of the pathophysiology of allergic rhinitis and asthma. Drugs targeting leukotriene-related molecules such as leukotriene synthase inhibitors and CysLT₁-receptor antagonists are widely used as safe and effective agents for the treatment of these diseases. The main limitation of anti-leukotriene drugs, however, is that there is a substantial proportion of patients who do not respond to these drugs. Therefore, identification of genetic and non-genetic factors that determine the pharmacologic response should further increase the usefulness of anti-leukotriene drugs. We undertook a multidirectional approach based on the assumption that the pharmacologic response to anti-leukotriene drugs is determined by factors related to pharmacokinetics such as drug metabolism, and pharmacodynamics such as the expression and function of leukotriene synthases and receptors. Among patients with asthma, we identified two genetic variations (polymorphisms) in the promoter of arachidonate 5-lipoxygenase and leukotriene C₄ synthase as possible factors to distinguish responders from non-responders to anti-leukotriene drugs. This pharmacogenetic approach might be useful to establish the basis of individualized treatment for patients with asthma as well as those with allergic rhinitis.