Effect of Montelukast on Time-Course of Exhaled Nitric Oxide in Asthma: Influence of LTC₄ Synthase A_-444C Polymorphism

Leukotrienes (LT) mediate inflammation in asthma. The fraction of exhaled nitric oxide (FE_NO) is thought to be a sensitive and reproducible method for assessing airway inflammation in asthmatics and the anti-inflammatory effects of drugs. A number of factors are known to contribute to intrapatient variation in FE_NO which can confound interpretation. The aims of this study were to characterize the time-course of FE_NO, determine the effect of montelukast on the time-course of FE_NO, and evaluate the influence of the LTC₄ synthase A_-444C polymorphism on montelukast-evoked changes in FE_NO. Following a 2-week run-in, 7 males and 5 females with asthma, 10-16 years old, received 5 or 10 mg of montelukast or an identical placebo at bedtime for 7 days in double-blind, crossover fashion, followed by a 7-day washout. FE_NO was quantified every 30 min for 3 or 6 hr at baseline and on days 1, 2, 3, and 7 of treatment. A time-averaged value for FE_NO was calculated (FE_NO*), and % changes in FE_NO* relative to baseline vs. time following placebo and montelukast were compared. The genotype of the A_-444C polymorphism was determined by PCR and RFLP. FE _NO varied markedly as a function of time in each patient. Time-averaged values of FE_NO (FE_NO*) during placebo and montelukast treatment were similar. Montelukast significantly reduced the slope of the % change in FE_NO* vs. time curve in heterozygotes (n = 4), but not in A/A homozygotes (n = 8). These data suggest that heterozygotes respond better to montelukast compared to A/A homozygotes, at least with respect to changes in FE_NO. We conclude that assessment of inflammation or the anti-inflammatory effects of drugs in asthma based on single determinations of FE_NO can be misleading. We further conclude that the A_-444C polymorphism in the LTC₄ synthase gene probably contributes to interpatient variability in montelukast-evoked changes in FE_NO* and warrants further study.