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Enantioselective disposition of (R,R)-formoterol, (S,S)-formoterol and their respective glucuronides in urine following single inhaled dosing and application to doping control.
Drug Test Anal. 2019 Jul; 11(7):950-956.DT

Abstract

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.

Authors+Show Affiliations

School of Medicine, University of Tasmania, Hobart, Australia.Section of Integrative Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Denmark. Department of Respiratory Medicine, Bispebjerg University Hospital, Denmark.School of Medicine, University of Tasmania, Hobart, Australia.Central Science Laboratory, University of Tasmania, Hobart, Australia.School of Medicine, University of Tasmania, Hobart, Australia.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30865387

Citation

Jacobson, Glenn A., et al. "Enantioselective Disposition of (R,R)-formoterol, (S,S)-formoterol and Their Respective Glucuronides in Urine Following Single Inhaled Dosing and Application to Doping Control." Drug Testing and Analysis, vol. 11, no. 7, 2019, pp. 950-956.
Jacobson GA, Hostrup M, Narkowicz CK, et al. Enantioselective disposition of (R,R)-formoterol, (S,S)-formoterol and their respective glucuronides in urine following single inhaled dosing and application to doping control. Drug Test Anal. 2019;11(7):950-956.
Jacobson, G. A., Hostrup, M., Narkowicz, C. K., Nichols, D. S., & Walters, E. H. (2019). Enantioselective disposition of (R,R)-formoterol, (S,S)-formoterol and their respective glucuronides in urine following single inhaled dosing and application to doping control. Drug Testing and Analysis, 11(7), 950-956. https://doi.org/10.1002/dta.2587
Jacobson GA, et al. Enantioselective Disposition of (R,R)-formoterol, (S,S)-formoterol and Their Respective Glucuronides in Urine Following Single Inhaled Dosing and Application to Doping Control. Drug Test Anal. 2019;11(7):950-956. PubMed PMID: 30865387.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Enantioselective disposition of (R,R)-formoterol, (S,S)-formoterol and their respective glucuronides in urine following single inhaled dosing and application to doping control. AU - Jacobson,Glenn A, AU - Hostrup,Morten, AU - Narkowicz,Christian K, AU - Nichols,David S, AU - Walters,E Haydn, Y1 - 2019/04/22/ PY - 2018/09/20/received PY - 2019/03/06/revised PY - 2019/03/07/accepted PY - 2019/3/14/pubmed PY - 2020/1/22/medline PY - 2019/3/14/entrez KW - SABA KW - arformoterol KW - beta2-agonist KW - enantiomer KW - metabolism SP - 950 EP - 956 JF - Drug testing and analysis JO - Drug Test Anal VL - 11 IS - 7 N2 - 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. SN - 1942-7611 UR - https://www.unboundmedicine.com/medline/citation/30865387/Enantioselective_disposition_of__RR__formoterol__SS__formoterol_and_their_respective_glucuronides_in_urine_following_single_inhaled_dosing_and_application_to_doping_control_ L2 - https://doi.org/10.1002/dta.2587 DB - PRIME DP - Unbound Medicine ER -