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A study on pharmacokinetic and pharmacodynamic effects of salbutamol-isomers
Linköping University, Department of Medicine and Care, Anaesthesiology. Linköping University, Department of Medicine and Care, Clinical Physiology. Linköping University, Faculty of Health Sciences.
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.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 766
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-27525Local ID: 12181ISBN: 91-7373-523-X (print)OAI: oai:DiVA.org:liu-27525DiVA: diva2:248077
Public defence
2003-01-17, Berzeliussalen, Hälsouniversitet, Linköping, 09:00 (Swedish)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-09-25Bibliographically approved
List of papers
1. Stereoselective pharmacokinetics of S-salbutamol after administration of the racemate in healthy volunteers
Open this publication in new window or tab >>Stereoselective pharmacokinetics of S-salbutamol after administration of the racemate in healthy volunteers
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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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26742 (URN)11337 (Local ID)11337 (Archive number)11337 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-09-25Bibliographically approved
2. Metabolism of salbutamol differs between asthmatic patients and healthy volunteers
Open this publication in new window or tab >>Metabolism of salbutamol differs between asthmatic patients and healthy volunteers
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2003 (English)In: Pharmacology and Toxicology, ISSN 0901-9928, Vol. 92, no 1, 27-32 p.Article in journal (Refereed) Published
Abstract [en]

Patients with asthma are a target group for medication with β2-agonists, often in combination with corticosteroids. Salbutamol is commonly marketed as racemate. R-Salbutamol carries β2-agonistic property whereas S-salbutamol does not. The racemate undergoes stereoselective sulphatisation by sulfotransferases mainly in the gut and liver, so that S-salbutamol rests for a longer time in the body and reaches higher plasma levels than R-salbutamol. Ten patients with mild stable asthma and at present without cortisone medication were given racemic salbutamol as ventoline 4 mg orally. Plasma and urine levels were estimated until 24 hr after ingestion. For comparison healthy volunteers were treated in the same way.The group of asthma patients was then treated with budesonide inhalations 800 μg daily for one week and the initial programme resumed. Non-cortisone-treated asthmatic patients displayed higher levels of both R- and S-salbutamol in plasma than did healthy volunteers after one single ingestion of racemic salbutamol (CMAX both comparisons P<0.05). Plasma levels of salbutamol isomers in cortisone-treated asthmatic patients resembled the levels in volunteers. The most plausible explanation for the discrepancy in values between asthmatic patients and volunteers is a defective metabolic function by asthmatic patients possibly enzymatic in origin.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26504 (URN)10.1034/j.1600-0773.2003.920105.x (DOI)11061 (Local ID)11061 (Archive number)11061 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-09-25Bibliographically approved
3. Preserved bronchial dilatation after salbutamol does not guarantee protection against bronchial hyperresponsiveness
Open this publication in new window or tab >>Preserved bronchial dilatation after salbutamol does not guarantee protection against bronchial hyperresponsiveness
2003 (English)In: Clinical Physiology and Functional Imaging, ISSN 1475-0961, E-ISSN 1475-097X, Vol. 23, no 1, 14-20 p.Article in journal (Refereed) Published
Abstract [en]

Racemic salbutamol, a β2-adrenoceptor agonist used for dilatation of airways, has recently been shown to induce lessened relaxation of bronchial smooth muscle and partial loss of bronchoprotection, seen as increased hyperresponsiveness, after regular treatment. The racemate undergoes stereo-selective disposition, giving higher plasma levels of S-salbutamol than that of bronchodilating R-salbutamol, thus raising S : R ratios after repeated administration. Our aim was to evaluate whether increased bronchial hyperresponsiveness (BHR) could be found even after 1 day of repeated salbutamol inhalations, with β2-receptor-induced bronchial smooth muscle relaxation remaining and whether this would be associated with plasma levels of either enantiomer. Fifteen patients with stable asthma, aged 19–54 years, were included in a randomized, cross-over study. An indirect bronchial challenge method was used [voluntary isocapnic hyperventilation of cold air (IHCA)], and airway condition tested by means of impulse oscillometry. Racemic salbutamol was inhaled three times during a 6-h period. IHCA was performed and plasma concentrations of enantiomers were measured 4 h after the last dose. Tests were also performed without preceding drug treatment. β2-Agonist-produced bronchial dilatation and protection persisted in the majority of the 15 patients 4 h after repeated inhalations of salbutamol during 1 day. In only two of the 15 patients we could trace increased BHR after salbutamol. Neither dilatation nor protection could be linked to plasma levels of either R- or S-salbutamol. The underlying mechanisms of BHR remain unknown and are dissociated from β2-receptor-mediated dilatation.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26503 (URN)10.1046/j.1475-097X.2003.00462.x (DOI)11060 (Local ID)11060 (Archive number)11060 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-09-25Bibliographically approved
4. Single-isomer R-salbutamol is not superior to the racemate ragarding bronchial hyperreactivity
Open this publication in new window or tab >>Single-isomer R-salbutamol is not superior to the racemate ragarding bronchial hyperreactivity
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Twenty-six patients with mild to moderate asthma were enrolled in a doubleblind, randomised, cross-over study. Bronchial response to provocation, given as isocapnic hyperventilation with cold air (IHCA), was measured before and after one week's medication with single isomer R-salbutamol and racemic R/S-salbutamol, respectively. Doses of 0.63 mg R-salbutamol or 1.25 mg R/S-salbutamol were inhaled by nebuliser three times daily dming medication-weeks. Impulse oscillometry (IOS) as well as forced expiratory volume dming one second (FEV1) were methods used to identify bronchial response to provocation. Two patients withdrew from the investigation due to side-effects, one from Rthe other from R,S-salbutamol.

The aim of this study was to investigate the effects from medication with R,S- and R-salbutamol on bronchial response to provocation.

Intra-individual differences of < 2% between days in baseline values, measured as total airway resistance (R5) by IOS and ≤ 1% measured as FEV1. indicated comparable resting bronchial conditions. After a week's medication no significant differences in airway responsiveness to provocation could be demonstrated irrespective of the medication used.

Neither regular medication with inhaled corticosteroids up to 800 mg/day nor any increase in ahway inflammation, was found to influence the results.

Plasmaconcentrations of R-salbutamol were intra-individually lower after R- than after R,S-salbutamol. Considerable amounts of S-salbutamol were retrieved in plasma after medication with pure R-salbutamol.

We conclude that we were unable to demonstrate favourable effects of R-salbutamol over R,S-salbutamol regarding response to provocation with cold air after medication of one week's duration.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-81908 (URN)
Available from: 2012-09-25 Created: 2012-09-25 Last updated: 2012-09-25Bibliographically approved

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