Journal of Clinical Pharmacy and Therapeutics (2003) 28, 235238

(R,S)-Salbutamol plasma concentrations in severe asthma

G. A. Jacobson*
PhD , F. V. Chong
BPharm (Hons) and R. Wood-Baker MBBS DM
MRCP FRACP

School of Pharmacy and School of Medicine, University of Tasmania, Tasmania, Australia

SUMMARY

INTRODUCTION

Objective: Salbutamol is commonly delivered as

a racemic mixture of pharmacologically active
(R)-salbutamol and inactive (S)-salbutamol.
This study investigated inactive (S)- and active
(R)-salbutamol plasma levels and their relationship to dose in patients with severe asthma.
Methods: Basic demographics, racemic-salbutamol dose in the preceding 24 h, lung function
tests at baseline and 1 h, and a 10 mL plasma
sample were obtained from subjects presenting to
the Department of Emergency Medicine with
acute asthma. Plasma determinations were carried
out using an LC-MS assay with solid phase
extraction.
Results: All patients (n = 5) had detectable levels
of drug in plasma with range of 0977 and
47274 ng/mL for (R)-salbutamol and (S)-salbutamol respectively. These were correlated to total
racemic salbutamol dose. The range of the
(S) : (R) ratio was 2052, with (R)-salbutamol
representing 1633% of the total plasma concentration, which did not correlate with total salbutamol dose.
Conclusion: Only a small fraction of total plasma
salbutamol concentration was found to consist of
active enantiomer in patients with an acute
severe exacerbation of asthma actively undergoing treatment with racemic-salbutamol. As a
result of the possible contribution of (S)-salbutamol to poor asthma control further enantioselective investigations are warranted in severe
asthma.

Salbutamol is most commonly delivered as a racemic mixture of pharmacologically active (R)-salbutamol and inactive (S)-salbutamol. It has been
suggested that (S)-salbutamol may play a role in
the deterioration of asthma control with regular use
(1).
(S)-Salbutamol increases airway responsiveness
to provocation in vitro and in guinea pigs (2, 3), and
may act as a functional antagonist to (R)-salbutamol (4). It possesses a longer half-life than active (R)-salbutamol and accumulates relative to
(R)-salbutamol with increasing duration of therapy
(59). The evidence of any clinical adverse effects in
humans from the (S)-enantiomer is less clear and
the subject of much debate (1012).
Salbutamol is metabolized by sulphotransferase
SULT1A3 (10) and this enzyme has been shown to
have significant inter-patient phenotypic variability.
It is controlled to varying extents by common genetic
polymorphisms (13, 14) and large inter-patient
variability in salbutamol urine levels have been
reported (15). Inter-patient differences in metabolism are further complicated by the stereoselective
nature of rac-salbutamol metabolism, with differences in clearance of (S)- and (R)-salbutamol potentially leading to a disproportionate ratio of inactive
(S) to active (R)-enantiomer in some patients. This
may explain why some patients are resistant to
high dose inhaled rac-salbutamol therapy (16, 17)
and patients suffering from asthma deaths have
been shown to have plasma concentrations of
rac-salbutamol 25 times higher than controls (18).
Studies examining enantiomer plasma levels of
rac-salbutamol after inhalation have previously
focussed on either healthy patients or patients with
mild-moderate controlled asthma (59). These
studies have been used to collect pharmacokinetic
data on (R)- and (S)-salbutamol and have been relatively short in duration. Unlike controlled pharmacokinetic studies, the majority of cases presenting
to the emergency department are patients with

Keywords: asthma, chiral, enantiomer, salbutamol

Received 9 January 2003, Accepted 31 March 2003

*Correspondence: Glenn A. Jacobson, School of Pharmacy,
University of Tasmania, GPO BOX 252-26, Hobart, Tas 7001,
Australia. Tel.: +61 3 6226 2190; fax: +61 3 6226 2870; e-mail:
glenn.jacobson@utas.edu.au

2003 Blackwell Publishing Ltd

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G. A. Jacobson et al.

deteriorating asthma control, usually with increased

reliance on short-acting inhaled b2-agonists therapy
in the hours, days or weeks leading up to their
presentation which would be expected to lead to
high plasma concentrations of drug.
The aim of this pilot study was to investigate the
plasma concentrations of (S)-salbutamol, (R)-salbutamol, and their ratio in adult patients who had
been using inhaled rac-salbutamol therapy and
presented to the emergency department with a
severe exacerbation of asthma.
MATERIALS AND METHODS

Subjects were recruited from outpatients with acute

asthma presenting to the Department of Emergency Medicine at the Royal Hobart Hospital, a 500
bed teaching hospital in Tasmania. Criteria for
inclusion were an acute exacerbation of severe
asthma, a peak expiratory flow rate (PEFR) and
forced expiratory volume in 1 s (FEV1) of 50%
predicted, inhaled rac-salbutamol use within the
previous 24 h, and age between 18 and 65 years.
Informed written consent was obtained from all
patients enrolled in the study which was approved
by the Southern Tasmania Health & Medical
Human Research Ethics Committee. Blood samples
(10 mL) were collected in potassium ethylenediaminetetraacetic acid tubes at least 30 min after the
last inhaled rac-salbutamol dose to ensure detectable levels and the plasma harvested by centrifugation and stored at )20 C until analysis.
Basic patient demographics and asthma drug
history over the last 24 h were recorded with dose
converted to a defined daily dose (DDD) for

standardization purposes using a DDD of 08 and

10 mg for inhaled aerosol/powder and solution
respectively. Rac-salbutamol use in the preceding
24 h was determined by reconciling patient
reported dose, obtained by questionnaire, and
physician or paramedic administered dose while
in or en route to the emergency department.
Determination of salbutamol enantiomers was
carried out using a previously reported LC-MS
assay, with a lower limit of quantification of
025 ng/mL and reproducibility coefficient of
variation of 65% (19).
The relationship between dose, and plasma concentration of racemate, enantiomers, and (S) : (R)
ratio was examined using linear regression. All statistical analyses were carried out using Statview
5.0.1 (SAS Institute Australia Pty Ltd, NSW, Australia). Results with P < 005 were considered
statistically significant.
RESULTS

Five subjects were recruited into the study (Table 1).

The correlation between rac-salbutamol dose in the
preceding 24 h and plasma concentration was
examined along with the correlation between racsalbutamol dose in the preceding 24 h and the S : R
enantiomer ratio (Fig. 1). There was good correlation between plasma levels and reported dose for
(S)-salbutamol (r2 086; P 002), (R)-salbutamol
(r2 086; P 002) and total rac-salbutamol
(r2 090; P 001) and poor correlation between
plasma (S) : (R) ratio and reported dose (r2 012;
P 056). The range of the ratio of (S) : (R) enantiomers was 2051.

Table 1. Patient demographics, asthma severity, rac-salbutamol dose and plasma concentrations
Patient

4a

5a

Age and sex

% Predicted PEFR (baseline)
% Predicted PEFR (60 min)
Inhaled rac-salbutamol dose in preceding 24 h (DDDs)
Plasma (R)-salbutamol (ng/mL)
Plasma (S)-salbutamol (ng/mL)
Total plasma rac-salbutamol (ng/mL)
S : R ratio

38 M
26
31
30
09
47
56
52

22 M
50
64
20
23
102
125
44

43 F
21
45
30
32
63
95
20

42 F
20
24
100
81
274
355
34

26 M
30
45
71
77
156
233
20

a
Admitted to hospital following presentation to the emergency department.
DDDs, defined daily doses.

2003 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 28, 235238

(R,S)-Salbutamol in severe asthma

6
5

40

4
30
3
20
2
10
0
0.0

S:R ratio in plasma

Racemic salbutamol plasma

concentration (ng/mL)

50

2.5

5.0

7.5

10.0

0
12.5

Salbutamol dose in the preceding 24 h (DDDs)

Fig. 1. Rac-salbutamol dose (defined daily dose) in the

preceding 24 h vs. plasma level (j; shown with linear
regression line of r2 0.90) and the ratio of (S)- to (R)salbutamol (s).

DISCUSSION

To the authors knowledge, these are the first

reported salbutamol enantiomer concentrations in
adult patients presenting to the emergency department with severe exacerbations of asthma. The
results of this study illustrate that a considerable
proportion of the rac-salbutamol in plasma may be
the pharmacologically inactive (S)-salbutamol.
With an (S) : (R) enantiomer ratio of 2052, only
between 16 and 33% of the plasma level measured
in this group of severe asthmatics was active drug.
This amount of (S)-salbutamol relative to (R)-salbutamol is a concern given previously reported in
vitro and animal findings of increases in airway
responsiveness and provocation associated with
(S)-salbutamol and possible functional antagonism
in humans. It is interesting that in this small group
of subjects, those who required hospitalization had
the highest concentrations of (S)-salbutamol, however, these patients also had the highest doses.
While a large (S) : (R) ratio might be expected
after cessation of salbutamol dosing because of the
slow elimination of (S)-salbutamol, or accumulation from administration of drug in the days leading up to presentation, a surprising finding was the
large (S) : (R) ratio in patients with an acute severe
asthma exacerbation while actively using inhaled
salbutamol to relieve worsening acute symptoms.
This study confirms what has been suggested from
controlled pharmacokinetic studies in healthy or
mild-moderate controlled asthmatics (59), that
(S)-salbutamol accumulates relative to (R)-salbuta-

237

mol after cumulative dosing during an acute

exacerbation.
Another interesting finding was that the racsalbutamol dose in the preceding 24 h (from a
reconciled combination of patient recall and medical records) showed good correlation with total
plasma levels of racemate and enantiomers. The
(S) : (R) ratio, however, did not, suggesting that
dose is not a major determinant of the (S) : (R)
ratio. This is consistent with phenotypic stereoselective metabolism playing a role in inter-patient
differences in enantiomer plasma levels rather than
temporal sampling bias related to dosing intervals.
The questions that arise are first, whether (S)salbutamol worsens asthma in this group of patients;
that is inter-patient differences in stereoselective
metabolism manifesting as severe asthma resulting
in a presentation to the emergency department and a
poor response to treatment. Secondly, whether this
group of severe asthmatics is representative of all
asthmatics from a metabolic perspective.
CONCLUSION

In patients with an acute severe asthma exacerbation actively undergoing treatment with rac-salbutamol, only a small fraction (1633%) of total
plasma concentration was found to consist of active
enantiomer. Further enantioselective investigations
of rac-salbutamol are warranted in severe asthma.
ACKNOWLEDGEMENTS

The authors wish to thank the Central Science

Laboratory at the University of Tasmania for the
LC-MS analysis of the plasma samples, the
Department of Emergency Medicine at the Royal
Hobart Hospital, and the Royal Hobart Hospital
Research Foundation for funding this project.
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