PHARMACOKINETICS AND EXTRAPULMONARY BETA(2) ADRENOCEPTOR ACTIVITY OF NEBULIZED RACEMIC SALBUTAMOL AND ITS R-ISOMERS AND S-ISOMERS IN HEALTHY-VOLUNTEERS

Background - Racemic salbutamol remains one of the most commonly used bronchodilators in the treatment of reversible airways obstruction. Da ta from animal and human studies suggest that the S-isomer, whilst con tributing no bronchodilator activity, may induce increased bronchial h yperreactivity 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 pharmacody namics at extrapulmonary beta(2) adrenoceptors when given by the inhal ed route to healthy volunteers. Methods - Twelve healthy volunteers of mean age 20.6 years were studied in a double blind, placebo controlle d, crossover design comparing cumulative doubling doses of nebulised R -salbutamol (R) and S-salbutamol (S) isomers (200 mu g/ 400 mu g/800 m u g/1600 mu g/3200 mu g) and racemic salbutamol (RS) (400 mu g/800 mu g/1600 mu g/ 3200 mu g/6400 mu g). Doses were administered at 20 minut e intervals (t(0)/t(20)/t(40)/t(60)/t(80)) and measurements were made of extrapulmonary beta(2) responses as an increase in finger tremor an d heart rate and fall in plasma potassium at baseline and each dose le vel (t(0)/t(20)/t(40)/t(60)/t(80)/t(100)). Plasma levels of salbutamol were measured at 15 minutes after each dose with a further sample at 30 minutes after the last dose (t(110)). Results - Pharmacodynamics sh owed 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 w ithin the administered dose range. No differences in responses were fo und between R-salbutamol and RS-salbutamol when compared on a 1:2 micr ogram basis. The effects of the S isomer were indistinguishable from t hose of placebo. For all beta(2) responses there were differences betw een R-salbutamol and S-salbutamol (for t(100) 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 th an R-salbutamol at 15 minutes after each dose, with R-salbutamol alrea dy being cleared and S-salbutamol reaching peak levels at 30 minutes a fter the last dose (at t(110)). There were higher plasma levels of R-s albutamol and S-salbutamol following administration of the respective isomers alone compared with their levels after administration of the r acemate, suggesting an influence of each isomer on the clearance of th e opposite isomer when given as a racemate. Conclusions - The S-isomer of salbutamol has no detectable activity at extrapulmonary beta(2) ad renoceptors whilst exhibiting higher plasma levels than the R-isomer, in keeping with greater clearance of R-salbutamol than S-salbutamol. I nhalation of R-salbutamol and RS-salbutamol produced dose-related beta (2) responses which were equivalent when compared on a 1:2 microgram b asis, despite higher plasma levels of R-salbutamol after administratio n of the R isomer than after administration of the racemate. Further d ose ranging studies are required at steady state to evaluate the pharm acokinetics of R-and S-salbutamol and their relative effects on bronch ial hyperreactivity when given on a regular basis to asthmatic subject s.