Stereoselective sulphate conjugation of salbutamol by human lung and bronchial epithelial cells

Eaton, E A; Walle, U K; Wilson, Hugh M.; Åberg, Gunnar; Walle, Thomas

doi:10.1111/j.1365-2125.1996.tb00183.x

Cited by 56 publications

(32 citation statements)

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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: 70%

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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mentioning

confidence: 70%

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

Fawcett¹,

Taylor²

1999

Eur Respir J

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“…The (R) -isomer is considered the active isomer because it binds to β 2 -receptor sites, produces bronchodilation, and has no effect or possibly reduces inflammatory stimuli 17 . Levalbuterol metabolizes about 8-times faster than SAlbuterol so it has shorter half-life than racemic salbutamol 18 .…”

Section: Discussionmentioning

confidence: 99%

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2013

IJPSR

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ABSTRACT:Background: β2-agonist drugs are frequently prescribed in asthmatics. Apart from bronchodilation they affect biochemical and physical parameters of the body. Method: Total 80 patients were divided into two groups. Group I (n=40) received Albuterol-2.5mg./2.5ml. TDS and Group II (n=40) received Levalbuterol-0.63mg./2.5ml, TDS via nebulizer for 4 weeks. Baseline and post-treatment estimation of biochemical parameters including, fasting and postprandial plasma glucose levels, serum Na+, serum K+ levels, lipid profile, Monitoring of systolic and diastolic BP and adverse drug effects evaluation were carried out. Results: Significantly changes were in serum lipid profile and blood glucose in both the groups but increase was more in group I. Serum K+ level was decreased significantly (p<0.05) in both groups but decrease was more in group I patients. The fasting and postprandial plasma glucose levels were significantly increased in both the groups but increase was more in group I. Systolic BP increases and diastolic BP decreases after administration of both drugs. There was no significant change observed in Serum Na+ level after administration of both drugs. After administration of both the drugs, an increase was observed in serum Lipid profile level. Adverse drug profile showed that Levalbuterol produce less adverse effects as compare to Albuterol. Conclusion: This study concludes that Levalbuterol is safer and it carries fewer incidences of adverse effects as compare to Albuterol.

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“…2. (2) The recommended daily intake of each extract was taken from the Physicians' Desk Reference (PDR) for Herbal Medicines 16) or the manufacturers' instructions for dietary supplements in Japan. The volume of gastrointestinal fluid was assumed to be 1 l.…”

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confidence: 99%

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Inhibitory Effects of Herbal Extracts on the Activity of Human Sulfotransferase Isoform Sulfotransferase 1A3 (SULT1A3)

Nagai

Fukamachi

Tsujimoto

et al. 2009

Biological & Pharmaceutical Bulletin

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Cytosolic sulfotransferases (SULTs) are a family of enzymes involved in the phase 2 detoxification of xenobiotics, including medicinal drugs such as ritodrine, salbutamol, minoxidil and paracetamol, 1,2) as well as in the sulfation of endogenous chemicals.3) Thus, inhibition of SULT activity may affect drug pharmacokinetics which in turn could cause adverse reactions.SULT1A3 and SULT1A1 are predominantly expressed in the intestinal epithelium and liver, respectively. 4) Therefore, food constituents that inhibit SULT1A3 may affect the absorption of drugs that undergo extensive presystemic sulfation, such as oral b 2 stimulants. We have previously encountered a case of adverse reaction associated with concomitant ingestion of grapefruit with the b 2 stimulant ritodrine, and demonstrated that several grapefruit constituents potently inhibit SULT1A3 and SULT1A1. 1,5) The intestinal and hepatic availabilities of ritodrine are estimated to be 0.68 and 0.54, 5) respectively, suggesting that one-third of orally administered ritodrine is considered to be eliminated by intestinal first pass and another one-third by the liver. As b 2 stimulants including ritodrine are predominantly conjugated with sulfate in humans, 6) SULTs are likely to play a key role in regulating the bioavailability of b 2 stimulants. Therefore, to avoid the above-mentioned interactions, it would be necessary to identify which foods inhibit SULT1A3 activity. However, there is little information about SULT1A3-mediated food-drug interactions, compared with the extensive studies of interactions mediated by other enzymes, such as cytochrome P450 (CYP) 3A4. 7,8) Flavonoids potently inhibit SULT1A3. 5,9,10) For example, we have reported that 10 mM quercetin and 100 mM catechin inhibit SULT1A3 activity by 50% and 70%, respectively. 5)The intestinal SULT1A3 may be potently inhibited by the ingestion of foods containing the above compounds at high Pharmacy and Life Science; 1432-1 Horinouchi, Hachiouji, Tokyo 192-0392, Japan. Received June 16, 2008 accepted October 20, 2008; published online October 23, 2008 Sulfotransferase 1A3 (SULT1A3) is a phase II detoxifying enzyme of xenobiotics predominantly expressed in the intestinal epithelium. Recent increase in the use of herbal extracts as dietary supplements may lead to an increase in the possibility of dietary supplement-drug interactions. The purpose of the present study was to investigate the effects of 18 herbal extracts on SULT1A3 activity and the possibility of interaction between medicinal drugs and herbal extracts. We examined the inhibitory potencies of 18 herbal extracts on the sulfation of dopamine, a typical substrate of SULT1A3, and ritodrine, a b b 2 stimulant, by human recombinant SULT1A3. The sulfation of dopamine was inhibited by extracts of banaba, green tea, Rafuma, grape seed, peanut seed coat, gingko biloba leaf, St. John's wort, gymnema and milkthistle. The IC 50 values of these herbal extracts were lower than the putative gastrointestinal concentration when the recommended dose was i...

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Stereoselective sulphate conjugation of salbutamol by human lung and bronchial epithelial cells

Cited by 56 publications

References 20 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?

Untitled

Inhibitory Effects of Herbal Extracts on the Activity of Human Sulfotransferase Isoform Sulfotransferase 1A3 (SULT1A3)

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