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Research ArticleArticle

Mass Balance and Metabolism of [3H]Formoterol in Healthy Men after Combined i.v. and Oral Administration–Mimicking Inhalation

Johan Rosenborg, Per Larsson, Kerstin Tegnér and Gösta Hallström
Drug Metabolism and Disposition October 1999, 27 (10) 1104-1116;
Johan Rosenborg
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Per Larsson
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Kerstin Tegnér
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Gösta Hallström
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Abstract

Mass balance and metabolism of formoterol were investigated in six healthy men in an open study. Mean age was 49.7 years (range: 40–63). Simultaneous oral (mean dose 88.6 nmol, 49.3 MBq) and i.v. (mean dose 38.2 nmol, 21.4 MBq) doses of tritium-labeled formoterol were administered. The combination of these two administrations was aimed at simulating the fate of inhaled formoterol. Total radioactivity was monitored for 24 h in blood plasma and for at least 4 days in urine and feces. Formoterol and metabolites were determined using liquid chromatography plus radiodetection, directly after centrifugation in urine and after sample workup in blood plasma and feces. Metabolites were identified in urine, sampled from two subjects, using liquid chromatography-electrospray ionization mass spectrometry. Mean total recovery was 86% of the administered formoterol dose, 62% in urine and 24% in feces. Tritiated water was generated and because its in vivo turnover is slow, the terminal decline of total radioactivity was slow and dose recovery was incomplete during the sampling period. Formoterol was conjugated to inactive glucuronides and a previously unidentified sulfate. The phenol glucuronide of formoterol was the main metabolite in urine. Formoterol was also O-demethylated and deformylated. Plasma exposure to these pharmacologically active metabolites was low.O-demethylated formoterol was seen mainly as inactive glucuronide conjugates and deformylated formoterol only as an inactive sulfate conjugate. Intact formoterol and O-demethylated formoterol dominated recovery in feces. Mean recovery of unidentified metabolites was 7.0% in urine and 2.0% in feces.

Footnotes

  • Send reprint requests to: Johan Rosenborg, Experimental Medicine, AstraZeneca R&D, S-221 87 Lund, Sweden. E-mail:Johan.Rosenborg{at}draco.se.astra.com

  • Part of the study was presented by Gösta Hallström in a key lecture at The 10th Nordic Conference on Mass Spectrometry, August 22–25, 1998, Umeå, Sweden under the title “LC-ESIMS/MS of Formoterol Metabolites in Man”.

  • Abbreviations used are::
    Met1
    O-demethylated formoterol
    3H2O
    tritiated water
    FG1
    phenol glucuronide of formoterol
    FG2
    benzyl glucuronide of formoterol
    FS
    sulfate of formoterol
    Met1G1
    glucuronide 1 of O-demethylated formoterol
    Met 1G2
    glucuronide 2 of O-demethylated formoterol
    Met2
    deformylated formoterol
    Met2S
    sulfate of deformylated formoterol
    XTOT
    quantified unidentified metabolites
    LC
    liquid chromatography
    MS
    mass spectometry
    ESI
    electrospray ionization
    SRM
    selected reaction monitoring (MS/MS technique in which one or a few precursor ions, plus expected characteristic product ions after collision-induced dissociation, are selected and continuously monitored
    AUC0–24h
    area under the curve of plasma concentration versus time up to 24 h (a measure of plasma exposure, calculated using the linear trapezoidal rule)
    CLR(0–24h)
    renal plasma clearance (amount excreted in urine up to 24 h divided by AUC0–24h
    • Received December 10, 1998.
    • Accepted June 16, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (10)
Drug Metabolism and Disposition
Vol. 27, Issue 10
1 Oct 1999
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Research ArticleArticle

Mass Balance and Metabolism of [3H]Formoterol in Healthy Men after Combined i.v. and Oral Administration–Mimicking Inhalation

Johan Rosenborg, Per Larsson, Kerstin Tegnér and Gösta Hallström
Drug Metabolism and Disposition October 1, 1999, 27 (10) 1104-1116;

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Research ArticleArticle

Mass Balance and Metabolism of [3H]Formoterol in Healthy Men after Combined i.v. and Oral Administration–Mimicking Inhalation

Johan Rosenborg, Per Larsson, Kerstin Tegnér and Gösta Hallström
Drug Metabolism and Disposition October 1, 1999, 27 (10) 1104-1116;
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