Pharmacokinetics and extrapulmonary beta 2 adrenoceptor activity of nebulised racemic salbutamol and its R and S isomers in healthy volunteers.
BACKGROUND
Racemic salbutamol remains one of the most commonly used bronchodilators in the treatment of reversible airways obstruction. Data from animal and human studies suggest that the S-isomer, whilst contributing no bronchodilator activity, may induce increased bronchial hyperreactivity and may explain the adverse effects of regular racemic salbutamol on asthmatic disease control. The purpose of this study was to evaluate the dose-response effects of racemic (+/-) salbutamol and its R(-) and S(+) isomers in terms of pharmacokinetics and pharmacodynamics at extrapulmonary beta 2 adrenoceptors when given by the inhaled route to healthy volunteers.


METHODS
Twelve healthy volunteers of mean age 20.6 years were studied in a double blind, placebo controlled, crossover design comparing cumulative doubling doses of nebulised R-salbutamol (R) and S-salbutamol (S) isomers (200 micrograms/400 micrograms/800 micrograms/1600 micrograms/3200 micrograms) and racemic salbutamol (RS) (400 micrograms/800 micrograms/1600 micrograms/3200 micrograms/6400 micrograms). Doses were administered at 20 minute intervals (t0/t20/t40/t60/t80) and measurements were made of extrapulmonary beta 2 responses as an increase in finger tremor and heart rate and fall in plasma potassium at baseline and each dose level (t0/t20/t40/t60/t80/t100). Plasma levels of salbutamol were measured at 15 minutes after each dose with a further sample at 30 minutes after the last dose (t110).


RESULTS
Pharmacodynamics showed dose related beta 2 responses for R-salbutamol and RS-salbutamol but not for the S isomer, and a plateau in response was not reached within the administered dose range. No differences in responses were found between R-salbutamol and RS-salbutamol when compared on a 1:2 microgram basis. The effects of the S isomer were indistinguishable from those of placebo. For all beta 2 responses there were differences between R-salbutamol and S-salbutamol (for t100 response as change from placebo); tremor (log units): R 0.74 vs S 0.03 (95% CI 0.39 to 1.03); fall in potassium (mmol/ 1): R 0.35 vs S -0.02 (95% CI 0.03 to 0.71). Pharmacokinetics showed consistently higher levels for S-salbutamol than R-salbutamol at 15 minutes after each dose, with R-salbutamol already being cleared and S-salbutamol reaching peak levels at 30 minutes after the last dose (at t110). There were higher plasma levels of R-salbutamol and S-salbutamol following administration of the respective isomers alone compared with their levels after administration of the racemate, suggesting an influence of each isomer on the clearance of the opposite isomer when given as a racemate.


CONCLUSIONS
The S-isomer of salbutamol has no detectable activity at extrapulmonary beta 2 adrenoceptors whilst exhibiting higher plasma levels than the R-isomer, in keeping with greater clearance of R-salbutamol than S-salbutamol. Inhalation of R-salbutamol and RS-salbutamol produced dose-related beta 2 responses which were equivalent when compared on a 1:2 microgram basis, despite higher plasma levels of R-salbutamol after administration of the R isomer than after administration of the racemate. Further dose ranging studies are required at steady state to evaluate the pharmacokinetics of R- and S-salbutamol and their relative effects on bronchial hyperreactivity when given on a regular basis to asthmatic subjects.
Lipworth
B J
BJ
Department of Clinical Pharmacology, Ninewells Hospital, Dundee, UK.
Clark
D J
DJ
Koch
P
P
Arbeeny
C
C
D000328:Adult; D000420:Albuterol / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D001993:Bronchodilator Agents / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D011188:Potassium / Q000097:blood; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects* / Q000502:physiology; D013237:Stereoisomerism; D014202:Tremor / Q000139:chemically induced
D001993:Bronchodilator Agents; D018343:Receptors, Adrenergic, beta-2; D000420:Albuterol; D011188:Potassium