Determination of (22R,S)budesonide in human plasma by automated liquid chromatography/thermospray mass spectrometry

Lindberg, Carl; Blomqvist, Ann; Paulson, Jan

doi:10.1002/bms.1200211102

Cited by 31 publications

(15 citation statements)

References 12 publications

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“…The plasma was separated by centrifugation (1,500×G) for 10 min and was then immediately frozen at -20°C until analysed. The assay of budesonide in plasma was based on a combination of liquid chromatography and mass spectrometry (LC-MS) [8].…”

Section: Methodsmentioning

confidence: 99%

Lung deposition of budesonide from Turbuhaler is twice that from a pressurized metered-dose inhaler P-MDI

Thorsson¹,

Edsbäcker²,

Conradson³

1994

Eur Respir J

375

167

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L Lu un ng g d de ep po os si it ti io on n o of f b bu ud de es so on ni id de e f fr ro om m T Tu ur rb bu uh ha al le er r¤ ¤ i is s t tw wi ic ce e t th ha atABSTRACT: The pulmonary and systemic availability of budesonide after inhalation from a dry powder inhaler, Turbuhaler®, and from a pressurized metered-dose inhaler (P-MDI) were compared in healthy volunteers. Two different methods were used to assess pulmonary availability: 1) calculated from the systemic availability corrected for an oral availability of 13% (n=24); and 2) after blocking of gastrointestinal absorption by administration of a charcoal suspension (n=13). An intravenous infusion of budesonide was used as a reference.The systemic availability of budesonide, calculated as a geometric mean and expressed as percentage of the metered dose, was 38% for Turbuhaler® and 26% for P-MDI. The pulmonary availability, calculated using the first method, was 32% and 15% for Turbuhaler® and P-MDI, respectively; and, using the second method, 32% and 18%, respectively.The results of the present study indicate that administration of budesonide via Turbuhaler® gives rise to a lung deposition which is approximately twice that of a P-MDI, with less variability, but that systemic availability is only increased by approximately 50%. Thus, the present data suggest that by administrating budesonide via Turbuhaler®, instead of a P-MDI, the same degree of asthma control can be achieved with a lower dose, which, in turn, reduces the risk of undesired systemic effects.

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Section: Methodsmentioning

confidence: 99%

Lung deposition of budesonide from Turbuhaler is twice that from a pressurized metered-dose inhaler P-MDI

Thorsson¹,

Edsbäcker²,

Conradson³

1994

Eur Respir J

375

167

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“…The plasma was separated by centrifugation (1500×g) for 10 min and was then imme-diately frozen at -20°C until analysis. The assay of budesonide in plasma was based on a combination of liquid chromatography and mass spectrometry [12].…”

Section: Methodsmentioning

confidence: 99%

Lung deposition of budesonide from a pressurized metered-dose inhaler attached to a spacer

Thorsson¹,

Edsbäcker²

1998

Eur Respir J

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In the treatment of asthma, inhaled formulations are commonly used to direct drugs to the lungs. The inhaled drug is deposited either in the upper respiratory tract or in the lungs. Exhaled drug generally constitutes a negligible part of the dose. The fraction deposited extrapulmonarily is eventually swallowed and absorbed from the gastrointestinal (GI) tract and will thus contribute to the systemic availability of the inhaled drug.Spacer devices between the actuator and the mouth are used to overcome the problem of co-ordinating actuation and inhalation from a pressurized metered-dose inhaler (pMDI). The particle size in the aerosol is reduced as evaporation of the propellant occurs [1][2][3]. Also, larger particles are preferentially deposited on the walls of the spacer. An increased fraction of small particles means that deposition in the oropharynx is decreased. In addition, lung deposition may be increased due to the fact that the velocity of the aerosol cloud is reduced before inhalation.The Nebuhaler® is a large-volume (750 mL) spacer intended for pMDIs of budesonide and terbutaline sulphate. Studies with 99m Tc-labelled Teflon™ particles, using γ-scintigraphic imaging techniques, have shown that the lung deposition, in asthmatic patients with airflow obstruction, increased from approximately 9% of the metered dose with a pMDI alone, to 21% after a single puff and 15% after multiple puffs when the pMDI was attached to a Nebuhaler® [4]. The lung deposition of 99m Tc-labelled terbutaline sulphate from a pMDI with a Nebuhaler® was 32% compared with 11% from a pMDI alone [5].Scintigraphic imaging is a commonly used technique to determine lung deposition after inhalation. Lung deposition can also be determined from urinary excretion of intact drug, provided that the contribution of orally deposited and subsequently swallowed drug can be accounted for, and that the drug is not metabolized in the lung [6]. One approach to accounting for swallowed drug is to prevent GI absorption by using concomitant oral administration of activated charcoal [7]. Another approach is to calculate the lung deposition from the systemic availability after inhalation by subtracting the estimated oral contribution [7].Budesonide is a potent glucocorticosteroid effective in the treatment of asthma. When given by inhalation, its antiasthmatic effect may be explained by a local pulmonary action [8]. No oxidative or reductive metabolism of budesonide has been noted in human lung homogenates [9]. The drug is rapidly and extensively absorbed [10]. Pharmacokinetic studies, performed in healthy subjects and asthmatic children, have shown that budesonide undergoes a high first-pass metabolism and has a low systemic availability (about 10%) after oral dosing [10,11]. Inhaled budesonide undergoes a rapid systemic uptake, with a time of maximum concentration of about 20 min. The systemic availability was found to be 26% from a pMDI and 38% Lung deposition of budesonide from a pressurized metered-dose inhaler attached to a spacer. L. Thorsson, S. E...

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“…Also, the presence of the two angular methyl groups on the steroid backbone should provide considerable steric hindrance to sulfation of the 11-hydroxyl group. In accordance with these observations, it has been shown that budesonide and hydrocortisone can be selectively acetylated chemically at the 21-hydroxyl group without affecting the more sterically hindered 11␤-hydroxyl group (Paulson and Lindberg, 1991;Lindberg et al, 1992). Moreover, budesonide is known to be conjugated with fatty acids in lung and liver apparently at the 21-hydroxyl group (Tunek et al, 1997).…”

Section: Meloche Et Almentioning

confidence: 84%

Sulfation of Budesonide by Human Cytosolic Sulfotransferase, Dehydroepiandrosterone-Sulfotransferase (DHEA-ST)

Meloche

Sharma²,

Swedmark³

et al. 2002

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Budesonide, a synthetic glucocorticosteroid, is used in the treatment of asthma and allergic reactions, rhinitis, and inflammatory bowel disease. It is distributed as a mixture of two epimers, 22R and 22S, and has a high ratio of topical to systemic activity due to extensive first-pass metabolism to metabolites with minimal activity. Previous studies have shown that the epimers are metabolized by the cytochrome P450 monooxygenase system. Metabolism and inactivation of the epimers by the phase II enzymes has not been well characterized. This study describes the conjugation of budesonide by human cytosolic sulfotransferases (SULTs). Seven human SULTs were analyzed to determine which were capable of catalyzing the sulfation of the epimers of budesonide. Only dehydroepiandrosterone-sulfotransferase (DHEA-ST, SULT2A1) was capable of forming a sulfated budesonide product. The epimeric forms of budesonide display different kinetic activities with the 22R epimer having a 3.5-fold greater rate of sulfation activity than the 22S epimer. The structure of budesonide shows two hydroxyl sites that are potential sites for sulfate conjugation, but analysis by mass spectrometry indicates the formation of only a monosulfated budesonide product. A modeling approach was used to define the site of sulfation as that of the 21-hydroxyl group. Although sulfation of budesonide by DHEA-ST may not be an important factor in its use as an antiasthmatic, intestinal and hepatic sulfation will be important for its proposed systemic use as an anti-inflammatory agent.Budesonide (Fig. 1) is a synthetic glucocorticosteroid used in the treatment of asthma, rhinitis, and inflammatory bowel diseases. It has a high ratio of topical to systemic activity partly due to extensive first-pass metabolism in the liver to metabolites with minimal activity (Clissold and Heel, 1984). Budesonide is distributed as a mixture of two epimers, 22R and 22S. The epimeric mixture is a 1:1 ratio whereby the 22R epimer has been reported to have a potency that is 2-to 3-fold greater than the 22S epimer based on topical activity (Brattsand et al., 1982).Previous in vitro studies with human liver microsomes have demonstrated that the budesonide epimers are differentially metabolized by the cytochrome P450 monooxygenase system. Budesonide 22R is metabolized by CYP3A4 to two major metabolites, 16␣-hydroxyprednisolone and 6␤-hydroxybudesonide, whereas the 22S epimer is only metabolized to one major metabolite, 6␤-hydroxybudesonide (Jonsson et al., 1995). These metabolites are also present in high amounts in plasma and urine after administration of budesonide to humans (P. Anderson, AstraZeneca, unpublished results). In contrast to phase I metabolism, only limited information on the metabolism of budesonide by the phase II drug-metabolizing enzymes is available.

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Determination of (22R,S)budesonide in human plasma by automated liquid chromatography/thermospray mass spectrometry

Cited by 31 publications

References 12 publications

Lung deposition of budesonide from Turbuhaler is twice that from a pressurized metered-dose inhaler P-MDI

Lung deposition of budesonide from Turbuhaler is twice that from a pressurized metered-dose inhaler P-MDI

Lung deposition of budesonide from a pressurized metered-dose inhaler attached to a spacer

Sulfation of Budesonide by Human Cytosolic Sulfotransferase, Dehydroepiandrosterone-Sulfotransferase (DHEA-ST)

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