Stereoselective pharmacokinetics of S-salbutamol after administration of the racemate in healthy volunteers

Schmekel, Birgitta; Rydberg, Irene; Norlander, Björn; Sjöswärd, Kerstin Naidu; Ahlner, Johan; Andersson, Rolf G. G.

doi:10.1034/j.1399-3003.1999.13f04.x

Cited by 57 publications

(51 citation statements)

References 21 publications

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“…It also seems likely that lung metabolism of inhaled salbutamol may be stereoselective, as suggested by in vitro studies [13] and by the results reported by SCHMEKEL et al [9]. Endotracheal aerosol administration resulted in higher plasma concentration of S-salbutamol but, in the absence of a comparative intravenous study in the same group of patients, it is difficult to quantify pre-systemic metabolism by the lung.…”

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confidence: 67%

“…R,S-salbutamol or R,S-fenoterol) has been extensively discussed [5,6], although no firm conclusions have been reached. In animal studies, the administration of racemates and distomers has been shown to enhance bronchial hyperresponsiveness [7,8], but this has not yet been demonstrated in human subjects during chronic dosing.The paper by SCHMEKEL et al [9] in this issue of the Journal contributes to the debate by providing further data related to the pharmacokinetics of salbutamol enantiomers. The results confirm earlier findings [10±12] that an oral dose of R,S-salbutamol is subject to extensive stereoselective first pass metabolism which leads to a high S:R ratio in the plasma, and to exposure to the more slowly cleared distomer in the absence of the eutomer.…”

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confidence: 99%

“…The paper by SCHMEKEL et al [9] in this issue of the Journal contributes to the debate by providing further data related to the pharmacokinetics of salbutamol enantiomers. The results confirm earlier findings [10±12] that an oral dose of R,S-salbutamol is subject to extensive stereoselective first pass metabolism which leads to a high S:R ratio in the plasma, and to exposure to the more slowly cleared distomer in the absence of the eutomer.…”

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confidence: 99%

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ß<SUB>2</SUB>-Agonist enantiomers: is there a glitch with the chiral switch?

Fawcett¹,

Taylor²

1999

Eur Respir J

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Current guidelines for the treatment of chronic asthma emphasize the use of anti-inflammatory medication and indicate that short-acting b 2 -agonists should only be taken on an as-needed basis [1]. This approach has been adopted because of the inflammatory nature of asthma and because, somewhat controversially, regular use of shortacting b 2 -agonists at best confers no distinct benefit on overall asthma control [2], and at worst may cause a deterioration [3].A number of possible mechanisms have been proposed to explain the adverse effects of chronic short-acting b 2 -agonist therapy [4], but the debate continues. One possible explanation currently under consideration is related to the fact that b 2 -agonists are chiral and are administered as racemic mixtures of a pharmacologically active eutomer (e.g. R-salbutamol) and an inactive distomer (e.g. S-salbutamol). The possibility that the distomers are selectively responsible for the toxic effects occurring during chronic treatment with racemates (e.g. R,S-salbutamol or R,S-fenoterol) has been extensively discussed [5,6], although no firm conclusions have been reached. In animal studies, the administration of racemates and distomers has been shown to enhance bronchial hyperresponsiveness [7,8], but this has not yet been demonstrated in human subjects during chronic dosing.The paper by SCHMEKEL et al. [9] in this issue of the Journal contributes to the debate by providing further data related to the pharmacokinetics of salbutamol enantiomers. The results confirm earlier findings [10±12] that an oral dose of R,S-salbutamol is subject to extensive stereoselective first pass metabolism which leads to a high S:R ratio in the plasma, and to exposure to the more slowly cleared distomer in the absence of the eutomer. In addition, it is shown that salbutamol administered by inhalation is also subject to stereoselective metabolism, and that multiple dosing by inhalation at clinically relevant time intervals leads to an increase in the S:R ratio as steady state is approached. Since there is some evidence that S-salbutamol acts as a functional antagonist to the active enantiomer [12], the potential for exposure to high levels of S-salbutamol provides an attractive alternative to tolerance to explain the reduction in bronchodilator efficacy during chronic dosing with racemic drug.The fact that salbutamol delivered by inhalation undergoes similar enantioselective first pass metabolism to that given orally is not surprising since inhalation of dry powder inevitably involves considerable oral ingestion. It also seems likely that lung metabolism of inhaled salbutamol may be stereoselective, as suggested by in vitro studies [13] and by the results reported by SCHMEKEL et al. [9]. Endotracheal aerosol administration resulted in higher plasma concentration of S-salbutamol but, in the absence of a comparative intravenous study in the same group of patients, it is difficult to quantify pre-systemic metabolism by the lung. In fact, the slow rate of absorption after endotracheal aerosol ...

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confidence: 67%

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confidence: 99%

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confidence: 99%

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ß<SUB>2</SUB>-Agonist enantiomers: is there a glitch with the chiral switch?

Fawcett¹,

Taylor²

1999

Eur Respir J

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“…When R , S -albuterol is given by inhalation, preferential retention of S -albuterol in the lung could lead to increasing concentrations of S -albuterol compared with R -albuterol over time [10]. Moreover, slower metabolism of S -albuterol compared to R -albuterol leads to maximum plasma concentrations and area under the curve of S -albuterol being 2–4 times higher than that of R -albuterol after inhalation of R , S -albuterol [27, 28]. Furthermore, after inhalation of R , S -albuterol, the elimination half-life of S -albuterol is approximately 50% longer than that of R -albuterol [29].…”

Section: Discussionmentioning

confidence: 99%

Enantiomer-Specific Effects of Albuterol on Airway Inflammation in Healthy and Asthmatic Cats

Reinero

Delgado

Spinka³

et al. 2009

Int Arch Allergy Immunol

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Background: Racemic (R,S)-albuterol is a 1:1 mixture of an R-enantiomer which has bronchodilatory and anti-inflammatory effects, and an S-enantiomer which is associated with increased airway hyperreactivity and proinflammatory effects. Proinflammatory effects of regularly inhalated and S-albuterol have not been studied in a whole-animal model. We hypothesized that regular administration of R,S-albuterol or S-albuterol, but not R-albuterol, would induce airway inflammation in healthy and asthmatic cats. Methods: Six healthy and 5 experimentally asthmatic cats were randomized to receive inhaled R,S-albuterol, S-albuterol, R-albuterol, or placebo (saline) twice daily for 2 weeks, followed by a 6-week washout before crossover to the next treatment. Bronchoalveolar lavage fluid was collected for cell counts and cytokine analysis prior to and at the end of each 2-week treatment. Results: Healthy and asthmatic cats receiving R,S- and S-albuterol had higher total lavage cell numbers (p = 0.04 and p = 0.02, respectively) than those receiving R-albuterol and placebo. The number of lavage eosinophils and the TNF-α bioactivity was higher in asthmatic cats receiving R,S- and S-albuterol compared with those receiving the other treatments (p = 0.03 and p = 0.004, respectively). In healthy cats, the number of lavage neutrophils was higher when they received R,S- and S-albuterol compared with other treatments (p = 0.04). Conclusion: Airway inflammation is induced in both healthy and asthmatic cats with regular inhalation of racemic and S-albuterol, but not with R-albuterol.

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“…Furthermore, pharmacokinetics of ingested salbutamol was significantly affected by inhaled budesonide in our asthmatic patients. The oral route of salbutamol racemate was deliberately chosen because of higher nominal standard doses and the pronounced disparity in S-and R-plasma levels after ingestion, giving high plasma levels of S-salbutamol (Schmekel et al 1999).…”

Section: Discussionmentioning

confidence: 99%

Metabolism of Salbutamol Differs between Asthmatic Patients and Healthy Volunteers

Sjöswärd¹,

Josefsson²,

Ahlner³

et al. 2003

Pharmacology & Toxicology

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Patients with asthma are a target group for medication with b2-agonists, often in combination with corticosteroids. Salbutamol is commonly marketed as racemate. R-Salbutamol carries b2-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 mg 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 PϽ0.05). 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.Racemic R,S salbutamol is used to relieve bronchial constriction, the b2-agonist effect being mediated by the Renantiomer. S-Salbutamol may also have a pharmacological effect, but distinctly different from that of R-salbutamol. In vitro experiments have indicated increased production of histamine in mast cells following S-salbutamol (Cho et al. 2001) and furthermore, increase of intracellular Ca 2π by muscarinic receptor activation has been shown in connection with the S-enantiomer (Mitra et al. 1998). The latter effect may be a possible link to enhanced bronchial hyperresponsiveness, suggested to occur after regular treatment with salbutamol in asthmatic patients, and suspected to be associated with the presence of S-salbutamol (Nelson 1999).Previous studies have shown a distinct stereoselective metabolism. Both R-and S-enantiomers are metabolised by sulfotransferases, mainly in the gut and liver (Walle et al. 1996);(Hartman et al. 1998) to inactive metabolites. Sulfotransferases work more effectively with the R-enantiomer, hence the bioavailability of S-isomer by far exceeds that of the R-enantiomer, resulting in S-to R-salbutamol ratio in plasma exceeding one after administration to human beings. Racemisation in the stomach accounts for a small degree (6%) of interconversion (Boulton & Fawcett 2001).Although a limited number of pharmacokinetic studies has been performed in asthmatic patients, most pharmacokinetic studies have been conducted on healthy volunteers. It seems more appropriate though, to study a target popula-

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Stereoselective pharmacokinetics of S-salbutamol after administration of the racemate in healthy volunteers

Cited by 57 publications

References 21 publications

ß<SUB>2</SUB>-Agonist enantiomers: is there a glitch with the chiral switch?

ß<SUB>2</SUB>-Agonist enantiomers: is there a glitch with the chiral switch?

Enantiomer-Specific Effects of Albuterol on Airway Inflammation in Healthy and Asthmatic Cats

Metabolism of Salbutamol Differs between Asthmatic Patients and Healthy Volunteers

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