Enantioselective disposition of (R,R)-formoterol, (S,S)-formoterol and their respective glucuronides in urine following single inhaled dosing and application to doping control

Glenn A Jacobson; Morten Hostrup; Christian K Narkowicz; David S Nichols; E Haydn Walters

doi:10.1002/dta.2587

Enantioselective disposition of (R,R)-formoterol, (S,S)-formoterol and their respective glucuronides in urine following single inhaled dosing and application to doping control

Glenn A Jacobson^*, Morten Hostrup, Christian K Narkowicz, David S Nichols, E Haydn Walters

^*Corresponding author af dette arbejde

August Krogh Sektionen for Human Fysiologi

6 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Drug Testing and Analysis
Vol/bind	11
Udgave nummer	7
Sider (fra-til)	950-956
Antal sider	7
ISSN	1942-7603
DOI	https://doi.org/10.1002/dta.2587
Status	Udgivet - jul. 2019

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Det Natur- og Biovidenskabelige Fakultet

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10.1002/dta.2587

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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. / Jacobson, Glenn A; Hostrup, Morten; Narkowicz, Christian K et al.

I: Drug Testing and Analysis, Bind 11, Nr. 7, 07.2019, s. 950-956.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

@article{99304598d68e45e69a0b86efaca6594e,

title = "Enantioselective disposition of (R,R)-formoterol, (S,S)-formoterol and their respective glucuronides in urine following single inhaled dosing and application to doping control",

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.",

keywords = "Faculty of Science, Arformoterol, Enantiomer, ADME, Metabolism, SABA, Beta2-agonist",

author = "Jacobson, {Glenn A} and Morten Hostrup and Narkowicz, {Christian K} and Nichols, {David S} and Walters, {E Haydn}",

year = "2019",

month = jul,

doi = "10.1002/dta.2587",

language = "English",

volume = "11",

pages = "950--956",

journal = "Drug Testing and Analysis",

issn = "1942-7603",

publisher = "JohnWiley & Sons Ltd",

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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

PY - 2019/7

Y1 - 2019/7

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.

AB - 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.

KW - Faculty of Science

KW - Arformoterol

KW - Enantiomer

KW - ADME

KW - Metabolism

KW - SABA

KW - Beta2-agonist

U2 - 10.1002/dta.2587

DO - 10.1002/dta.2587

M3 - Journal article

C2 - 30865387

SN - 1942-7603

VL - 11

SP - 950

EP - 956

JO - Drug Testing and Analysis

JF - Drug Testing and Analysis

IS - 7

ER -

Enantioselective disposition of (R,R)-formoterol, (S,S)-formoterol and their respective glucuronides in urine following single inhaled dosing and application to doping control

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