Metabolism of Salbutamol Differs between Asthmatic Patients and Healthy Volunteers

Abstract

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-

Levalbuterol versus albuterol

“…Thus, performance of longer trials is desirable to better discern the effects of (S)-albuterol under chronic conditions because it has been shown that severe asthma patients (who are more likely to use their racemic albuterol inhaler frequently) can have two to fi ve times higher levels of (S)-albuterol in their plasma [60]. Also, steroid-naïve asthma patients have high serum levels of (S)-albuterol compared with steroid-treated asthma patients and healthy volunteers [14,16], again perhaps because of issues related to control of asthma symptoms.…”

“…In this regard, one important characteristic of (S)-albuterol is its slower pharmacokinetic profi le (it is metabolized as much as 12 times slower than levalbuterol) [10,11]. This occurs in part because of its delayed sulfation and elimination by enzymes preferentially specifi c for levalbuterol [12][13][14][15], which results in differences in circulating levels of each isomer after administration of racemic albuterol [16]. It has been shown that circulating levalbuterol is undetectable within 2 to 3 hours after a single dose of inhaled racemic albuterol, whereas (S)-albuterol levels persist for as long as 12 hours and may be preferentially retained in the lungs [17,18].…”

Induction of human sulfotransferase 1A3 (SULT1A3) by glucocorticoids

“…It is indeed of interest to note that the pharmacokinetics of ingested salbutamol was affected by the GR ligand, budesonide. The plasma concentrations of salbutamol were lowered significantly in patients after administration of budesonide and this was attributed to the changes in metabolism of salbutamol (Naidu Sjosward et al, 2003). Since salbutamol is metabolized exclusively by SULT1A3 to the inactive sulfate conjugate (Walle et al, 1993b), it is likely that induction of SULT1A3 activity by the GR ligand, budesonide led to increased metabolism and hence lowered plasma levels.…”

Levosalbutamol as alternative to drugs on the basis of racemic salbutamol: Review of the results of pre-clinical research

“…Кверцетин ингибирует сульфатирование R-сальбутамола, причем интенсивность ингибиторного действия на одиндва порядка выше в двенадцатиперстной кишке по сравнению с печенью (Pacifici, 2004). В результате S-сальбутамол более длительный период персистирует в организме и достигает значимо более высоких концентраций в плазме крови по сравнению с R-энантиомером (Sjöswärd et al, 2003). SULT1A3 относительно резистентен к ингибиторным эффектам мефенамовой кислоты, салициловой кислоты и кверцетина (Pacifici, 2004).…”