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Mass balance and metabolism of 3H-formoterol in healthy men after combined i.v. and oral administration - mimicking inhalation
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
1999 In: Drug Metab Dispos, Vol. 27, 1104-1116 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
1999. Vol. 27, 1104-1116 p.
URN: urn:nbn:se:uu:diva-89461OAI: oai:DiVA.org:uu-89461DiVA: diva2:160910
Available from: 2001-10-03 Created: 2001-10-03Bibliographically approved
In thesis
1. Clinical-Pharmacokinetic Aspects of Prolonged Effect Duration as Illustrated by β2-Agonists
Open this publication in new window or tab >>Clinical-Pharmacokinetic Aspects of Prolonged Effect Duration as Illustrated by β2-Agonists
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Regularity is a key element of maintenance drug treatment; compliance is crucial for treatment success. Once- or twice-daily intake of a drug is always easier to comply with than regimens requiring more frequent dosing. Bronchodilating treatment was used as an example to illustrate how sustained duration of effect can be achieved by two different approaches: oral administration of the terbutaline prodrug bambuterol and inhalation of formoterol. Bioanalytical methods were employed to monitor the kinetic fate of bambuterol and formoterol in plasma, urine, or faeces. Generated terbutaline in plasma was used as a marker of effect for bambuterol. Established clinical laboratory tests were used to assess local and systemic effects of inhaled formoterol compared with salbutamol.

Recommended doses of bambuterol, 10-20 mg once daily in adults, normally produced plasma concentrations of the active moiety terbutaline within therapeutically relevant limits. Dose proportionality for terbutaline makes dosing with bambuterol predictable. Compared with adults, children should be given higher doses than indicated by their lower body weight. Pharmacokinetic analysis indicated that absorption of bambuterol was slow and multi-phasic and that slow biotransformation to terbutaline occurred both presystemically and systemically.

Systemically circulating formoterol was rapidly eliminated, the inactive (S;S)-formoterol more rapidly than the active (R;R)-formoterol. An inactive phenol glucuronide was the main metabolite, and a previously unknown sulphate metabolite was discovered. Duration of systemically mediated cardiovascular or metabolic side-effects of inhaled formoterol seemed not to differ from those of an inhaled systemically equieffective dose of salbutamol. There was a trend suggesting that the magnitude of systemic side-effects may be less pronounced after inhalation of formoterol compared with a locally equieffective dose of inhaled salbutamol.

Both approaches to sustaining stimulation of β2-adrenoceptors have their pros and cons. Bambuterol can be dosed orally once daily, but full effect is reached slowly. The effect of formoterol is reached within a few minutes, but administration must occur via the lungs, often twice daily. Both treatments, however, give 24-h symptom relief during regular treatment.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2001. 41 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 256
Pharmaceutical biosciences, Farmaceutisk biovetenskap
National Category
Pharmaceutical Sciences
Research subject
urn:nbn:se:uu:diva-1399 (URN)91-554-5099-7 (ISBN)
Public defence
2001-09-21, Uppsala Biomedical Center, lecture hall B41, Uppsala, 10:15
Available from: 2001-10-03 Created: 2001-10-03Bibliographically approved

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