School of Medicine, University of Tasmania, Hobart, Australia.
Section of Integrative Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Denmark.
Drug Test Anal. 2019 Jul;11(7):950-956. doi: 10.1002/dta.2587. Epub 2019 Apr 22.
Formoterol is a long-acting beta2-adrenoceptor agonist (LABA) used for the treatment of asthma and exercise-induced bronchoconstriction. Formoterol is usually administered as a racemic (rac-) mixture of (R,R)- and (S,S)-enantiomers. While formoterol is restricted by the World Anti-Doping Agency (WADA), inhalation of formoterol is permitted to a predetermined dose (54 μg/24 hours) and a urine threshold of 40 ng/mL. However, chiral switch enantiopure (R,R)-formoterol is available, effectively doubling the therapeutic advantage for the same threshold. The aim of this study was to investigate whether formoterol exhibits enantioselective urinary pharmacokinetics following inhalation. Six healthy volunteers were administered a 12 μg inhaled dose of rac-formoterol. Urine was collected over 24 hours and analyzed by enantioselective ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) assay. Total (free drug plus conjugated metabolite) median (min-max) rac-formoterol urine levels following inhalation were 1.96 (1.05-13.4) ng/mL, 1.67 (0.16-9.67) ng/mL, 0.45 (0.16-1.51) ng/mL, 0.61 (0.33-0.78) ng/mL, and 0.17 (0.08-1.06) ng/mL at 2, 4, 8, 12, and 24 hours, respectively, well below the 2019 urine threshold. The proportion of conjugation differed between enantiomers with glucuronide conjugation much greater for (R,R)-formoterol (around 30%-60% of total) compared to (S,S)-formoterol (0%-30%). There was clear evidence of inter-individual enantioselectivity observed in the ratios of (R,R):(S,S)-formoterol, where (S,S)- was predominant in free formoterol, and (R,R)- predominant in the conjugated metabolite. In conclusion, rac-formoterol delivered by inhalation exhibits enantioselective elimination in urine following single-dose administration. Enantioselective assays should be employed in doping control to screen for banned beta2-agonist chiral switch products such as (R,R)-formoterol, and total hydrolyzed rac-formoterol is warranted to account for inter-individual differences in enantioselective glucuronidation.
福莫特罗是一种长效β2-肾上腺素受体激动剂（LABA），用于治疗哮喘和运动诱发的支气管收缩。福莫特罗通常以（R,R）-和（S,S）-对映异构体的外消旋（rac-）混合物的形式给药。虽然福莫特罗受到世界反兴奋剂机构（WADA）的限制，但吸入福莫特罗的剂量（54μg/24 小时）和尿液阈值为 40ng/mL 是允许的。然而，手性转换对映纯（R,R）-福莫特罗可用，在相同的阈值下，其治疗优势实际上增加了一倍。本研究旨在探讨吸入后福莫特罗是否表现出尿药动力学的对映选择性。六名健康志愿者接受了 12μg 吸入剂量的 rac-福莫特罗。收集 24 小时尿液，并用对映体选择性超高效液相色谱-串联质谱（UPLC-MS/MS）分析。吸入后，rac-福莫特罗尿液总（游离药物加结合代谢物）中位数（最小-最大）分别为 2 小时、4 小时、8 小时、12 小时和 24 小时时为 1.96（1.05-13.4）ng/mL、1.67（0.16-9.67）ng/mL、0.45（0.16-1.51）ng/mL、0.61（0.33-0.78）ng/mL 和 0.17（0.08-1.06）ng/mL，均远低于 2019 年的尿液阈值。对映体之间的结合比例不同，（R,R）-福莫特罗的葡萄糖醛酸结合（约 30%-60%）远大于（S,S）-福莫特罗（0%-30%）。在（R,R）：（S,S）-福莫特罗的比例中，观察到明显的个体间对映选择性，其中（S,S）-福莫特罗以游离形式为主，（R,R）-福莫特罗以结合代谢物为主。总之，单次给药后，吸入的 rac-福莫特罗在尿液中表现出对映选择性消除。在兴奋剂控制中，应使用对映体选择性检测来筛选禁用的β2-激动剂手性转换产品，如（R,R）-福莫特罗，并且需要总水解 rac-福莫特罗来解释对映体选择性葡萄糖醛酸化的个体间差异。
