liu.seSearch for publications in DiVA
Change search
ReferencesLink to record
Permanent link

Direct link
Stereoselective pharmacokinetics of S-salbutamol after administration of the racemate in healthy volunteers
Linköping University, Department of Medicine and Care, Clinical Physiology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Care, Anaesthesiology. Linköping University, Faculty of Health Sciences.
Show others and affiliations
1999 (English)In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 13, no 6, 1230-1235 p.Article in journal (Refereed) Published
Abstract [en]

Racemic R,S-salbutamol is taken to relieve bronchial constriction. Only the R-enantiomer has bronchodilating properties. The S-enantiomer has been proposed to cause in vitro bronchial hyperreactivity in guinea-pigs. Stereoselective elimination of salbutamol has been shown, with S-salbutamol being eliminated at a slower rate than R-salbutamol. This study questioned whether rates of stereoselective elimination were similar after oral or lung delivery, and whether the S:R ratio would increase after repeated inhalations in a situation resembling a common clinical use. Eighteen healthy volunteers received single-dose racemic salbutamol as a solution instilled in the trachea during anaesthesia, as inhaled micronized powder and/or as ingested tablets. Five volunteers inhaled repeated doses of racemic salbutamol. Concentrations in plasma and urine were measured using a technique which allowed chiral separation of samples with concentrations as low as 0.1 ng·mL -1. The bioavailability of S-salbutamol was significantly higher than that of R-salbutamol after the different modes of administration. Stereoselective elimination was more pronounced after oral administration than after inhalation. Repeated inhalations resulted in successive increases in the S:R ratio as steady state was approached. In conclusion, the clinical consequences of increasing plasma concentrations of S-salbutamol need to be further assessed.

Place, publisher, year, edition, pages
1999. Vol. 13, no 6, 1230-1235 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-26742Local ID: 11337OAI: diva2:247292
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-09-25Bibliographically approved
In thesis
1. A study on pharmacokinetic and pharmacodynamic effects of salbutamol-isomers
Open this publication in new window or tab >>A study on pharmacokinetic and pharmacodynamic effects of salbutamol-isomers
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [sv]

Astma är en kronisk inflammatorisk luftvägssjukdom som förekommer i hög - och enligt rapporter ökande - frekvens världen över. Defmitionen av astma inkluderar varierande luftvägsobstruktion och ökad bronkiell reaktivhet gentemot olika stimuli. Medicinering mot astma består vanligtvis av bronkvidgande beta-receptor-agonister som ofta kombineras med inflammationshärmnande medel såsom kortikosteroider.

Salbutamol. en beta-receptor-agonist har två isomerer. R-salbutamol och S-salbutamol, och används ofta som racemat. Bronk-vidgning åstadkommes enbart av R-isomeren medan S-salbutamol har misstänkis öka bronkiell hyperreakiivitet. Salbutamol genomgår stereoselektiv metabolisering. som gynnar R-enantiomeren. Detta medför att S-enantiomeren kvarstannar längre i kroppen och att S/R-kvoten i plasma överstiger ett.

Farmakokinetiska studier genomfördes på 22 friska frivilliga försökspersoner. Resultatet av stereoselektiv metabolisering sågs mera uttalat efter nedsväljning av salbutan10lracemat än efter inhalation eller endotrakeal tillförsel av preparatet. Upprepade inhalationer ledde till ökande S/R-kvoter i plasma. Båda isomererna återfanns i högre halter i plasma från icke kortisonbehandlade astmapatienter än från friska personer efter nedsväljning av racerniskt salbutamol. Efter en veckas kortisonbehandling (budesonid) åtföljt av salbutamolracemat. låg astmapatienternas plasmakoncentrationer lägre än tidigare och liknade dem hos friska icke-kortisonbehandlade personer.

Femton patienter med astma utvaldes slumpmässigt i ett crossover försök antingen till behandling med racerniskt salhutamol (tre doser tmder sex timmar) eller till att vara utan behandling. Fyra tinm1ar efter inhalation var tolv av fjorton patienter fortfarande bronkvidgade och också skyddade mot effeki av hyperventilatorisk bronkprovokation. Två patienter visade tecken till ökat svar på provokation trots vidgade bronker jämfört med en dag utan behandling. Plasmahalter av isomerer gav ingen förklaring till dessa skilmader i svar på provokation. Tjugotvå patienter med astma ingick i en annan randomiserad crossover studie avseende behandling med inhalationer av racemiski salhutamol och ren R-salbutamol. Sex tinm1ar efter sista dos av endera läkemedlet hade bronkvidgningen upphört hos alla patienter. R-salbutamol visade sig inte vara överlägset salbutamolracemat som skydd mot bronkiell provokation - tvärtom tyckies den kraftigaste hyperreaktiviteten föreligga efter medicinering med rent R-salbutamol. Plasma från blodprover tagna efter medicinering med ren R-salbutamol imlehöll avsevärda mängder av s-isomeren och tenderade att imlehålla lägre halt av R-isomeren än efter tillförsel av sammla mängd R-salbutamol som racemat. Man kunde spåra ett samband mellan detta och ökad bronkiell reaktivitet.

Sammanfattning: Avsevärda inter-individuella skillnader föreligger gällande stereoselektiv metabolisering av salhutamol och farmakodynanuska konsekvenser av medicinering. De här redovisade studierna visar på behovet av fortsatta tmdersökningar.

Abstract [en]

Asthma is a common chronic inflammatory airway disease with reported increasing incidence over the world. Definition of asthma includes variable obstruction of the airways and increase in bronchial responsiveness to various stimuli. Drug treatment for asthma traditionally consists of bronchodilatory beta-receptor-agonists, often in combination with anti-inflammatory remedies such as corticosteroids.

Salbutamol, a beta-receptor-agonist, has two stereo-isomers, R-salbutamol and Ssalbutamol, and is mostly given as a racemate. The ability for bronchodilation rests in the R-isomer, whereas the S-isomer has been suspected to increase bronchial hyperresponsiveness. Salbutamol m1dergoes stereo-selective metabolism favouring the Renantiomer. This leaves the S-enantiomer to rest for longer time in the body, and gives SiR-ratios in plasma exceeding one.

Pharmacokinetic stndies were performed in twenty-two healthy volunteers. Stereoselective metabolism was more pronounced after oral delivery than after inhalation or endotracheal deposition of the racemate. Repeated inhalations gave rise to increasing SiR-ratios in plasma. Higher plasma-levels of both isomers were obtained in non-cortisone-treated patients with asthma compared to healthy volunteers after ingestion of racemic salbutamol. Following cortisone-treatment (budesonide) for one week the plasma-levels of asthmatic patients were lowered and resembled those of non-treated volunteers.

Fifteen patients with asthma were randomly assigned to three repeated inhalations of racemic salbutamol over six hours or to "'non-treatment" in a crossover fashion. Twelve out of fomteen patients were still bronchodilated and also protected against the impact of a hyperventilation challenge four hours after inhalations. Two patients showed signs of increased response to provocation in spite of dilatation, compared to a non-treatment day. Plasma-levels of isomers did not explain these differences in response. Twenty-four patients with asthma were randomly assigned to one week's inhalation medication with either racemate or pure R-salbutamol in another crossover study. Six hours after the last inhaled dose, bronchodilation had faded away in all patients. R-salbutamol did not prove superior to racemate in protecting against a hyperventilation-challenge - on the contrary the most intensive hyper-responsiveness was seen after medication with the R-enantiomer. Plasma-levels drawn after medication with the pme R-isomer held considerable amounts of the S-isomer and tended to hold lower levels of the R-isomer than when equal amounts or R-salbutamol was given as racemate. A connection could be traced between this and increased hyper-responsiveness.

Conclusion: Considerable inter-individual variations in stereoselective metabolism of salbutamol and in pharmacodynamic consequences of medication were found. These studies point at the necessity for further investigations.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2003. 51 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 766
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-27525 (URN)12181 (Local ID)91-7373-523-X (ISBN)12181 (Archive number)12181 (OAI)
Public defence
2003-01-17, Berzeliussalen, Hälsouniversitet, Linköping, 09:00 (Swedish)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-09-25Bibliographically approved

Open Access in DiVA

No full text

Other links


Search in DiVA

By author/editor
Schmekel, BirgittaRydberg, IreneNorlander, BjörnAhlner, JohanAndersson, Rolf
By organisation
Clinical PhysiologyFaculty of Health SciencesPharmacologyClinical PharmacologyAnaesthesiology
In the same journal
European Respiratory Journal
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Total: 79 hits
ReferencesLink to record
Permanent link

Direct link