Lima John J
Nemours Children's Clinic, Centers for Clinical Pediatric Pharmacology & Pharmacogenetics, Jacksonville, Florida 32207, USA.
Mol Diagn Ther. 2007;11(2):97-104. doi: 10.1007/BF03256228.
Despite advances in treatment, asthma continues to be a significant health and economic burden. Although asthma cannot be cured, several drugs, including beta2 agonists, corticosteroids, and leukotriene (LT) modifiers, are well tolerated and effective in minimizing symptoms, improving lung function, and preventing exacerbations. However, inter-patient variability in response to asthma drugs limits their effectiveness. It has been estimated that 60-80% of this inter-patient variability may be attributable to genetic variation. LT modifiers, in particular, have been associated with heterogeneity in response. These drugs exert their action by inhibiting the activity of cysteinyl leukotrienes (CysLTs), which are potent bronchoconstrictors and pro-inflammatory agents. Two classes of LT modifiers are 5-lipoxygenase (ALOX5) inhibitors (zileuton) and leukotriene receptor antagonists (LTRAs) [montelukast, pranlukast, and zarfirlukast]. LT modifiers can be used as alternatives to low-dose inhaled corticosteroids (ICS) in mild persistent asthma, as add-on therapy to low- to medium-dose ICS in moderate persistent asthma, and as add-on to high-dose ICS and a long-acting ss2 agonist in severe persistent asthma. At least six genes encode key proteins in the LT pathway: arachidonate 5-lipoxygenase (ALOX5), ALOX5 activating protein (ALOX5AP [FLAP]), leukotriene A4 hydrolase (LTA4H), LTC4 synthase (LTC4S), the ATP-binding cassette family member ABCC1 (multidrug resistance protein 1 [MRP1]), and cysteinyl leukotriene receptor 1 (CYSLTR1). Studies have reported that genetic variation in ALOX5, LTA4H, LTC4S, and ABCC1 influences response to LT modifiers. Plasma concentrations of LTRAs vary considerably among patients. Physio-chemical characteristics make it likely that membrane efflux and uptake transporters mediate the absorption of LTRAs into the systemic circulation following oral administration. Genes that encode efflux and uptake transport proteins harbor many variants that could influence the pharmacokinetics, and particularly the bioavailability, of LTRAs, and could contribute to heterogeneity in response. In the future, large, well designed clinical trials studying the pharmacogenetics of LT modifiers in diverse populations are warranted to determine whether a genetic signature can be developed that will accurately predict which patients will respond.
尽管在治疗方面取得了进展，但哮喘仍然是一个重大的健康和经济负担。虽然哮喘无法治愈，但包括β2激动剂、皮质类固醇和白三烯（LT）调节剂在内的几种药物耐受性良好，在减轻症状、改善肺功能和预防病情加重方面有效。然而，患者对哮喘药物反应的个体差异限制了它们的有效性。据估计，这种患者间差异的60 - 80%可能归因于基因变异。特别是LT调节剂，已与反应的异质性相关。这些药物通过抑制半胱氨酰白三烯（CysLTs）的活性发挥作用，CysLTs是强效支气管收缩剂和促炎剂。两类LT调节剂是5 - 脂氧合酶（ALOX5）抑制剂（齐留通）和白三烯受体拮抗剂（LTRAs）[孟鲁司特、普仑司特和扎鲁司特]。LT调节剂可在轻度持续性哮喘中用作低剂量吸入性皮质类固醇（ICS）的替代品，在中度持续性哮喘中作为低至中剂量ICS的附加治疗，在重度持续性哮喘中作为高剂量ICS和长效β2激动剂的附加治疗。至少有六个基因编码LT途径中的关键蛋白：花生四烯酸5 - 脂氧合酶（ALOX5）、ALOX5激活蛋白（ALOX5AP [FLAP]）、白三烯A4水解酶（LTA4H）、白三烯C4合成酶（LTC4S）、ATP结合盒家族成员ABCC1（多药耐药蛋白1 [MRP1]）和半胱氨酰白三烯受体1（CYSLTR1）。研究报告称，ALOX5、LTA4H、LTC4S和ABCC1的基因变异会影响对LT调节剂的反应。患者之间LTRAs的血浆浓度差异很大。物理化学特性使得膜转运蛋白的外排和摄取可能介导口服给药后LTRAs吸收进入体循环。编码外排和摄取转运蛋白的基因有许多变体，可能影响LTRAs的药代动力学，特别是生物利用度，并可能导致反应的异质性。未来，有必要开展大规模、精心设计的临床试验，研究不同人群中LT调节剂的药物遗传学，以确定是否可以开发出一种基因特征，准确预测哪些患者会有反应。
