Pharmacokinetics of inhaled salbutamol in patients with cystic fibrosis versus healthy young adults

Vaisman, Nachum; Koren, Gideon; Goldstein, Dan; Canny, Gerard J.; Tan, Yok K.; Soldin, Steven J.; Pencharz, Paul B.

doi:10.1016/s0022-3476(87)80218-4

Cited by 22 publications

(16 citation statements)

References 5 publications

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“…It can generally be considered that the airway disease state of asthma patients may alter the pulmonary disposition and absorption of salmeterol, similarly to that observed with other β 2 -agonists (Lipworth & Clark, 1997;Vaisman et al, 1987). However, relatively limited data have been published on the PK behavior of salmeterol.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic analysis of inhaled salmeterol in asthma patients: Evidence from two dry powder inhalers

Soulele

Macheras

Karalis

2017

Biopharm & Drug Disp

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Salmeterol (SAL) is a long-acting β2-adrenergic agonist, which is widely used in the therapy of asthma. The aim of this study was to investigate the pharmacokinetics (PK) of inhaled salmeterol in asthma patients using two different dry powder inhalers. This analysis was based on data from 45 subjects who participated in a two-sequence, four-period crossover bioequivalence (BE) study after single administration of the test (T) and reference (R) products. In order to mimic more closely the real treatment conditions, activated charcoal was not co-administered. Plasma concentration-time (C-t) data were initially analysed using classic non-compartmental PK approaches, while the main objective of the study was to apply population PK modeling. The relative fraction of the dose absorbed via the lungs (R ) was set as a parameter in the structural model. The plasma C-t profiles of salmeterol showed a biphasic time course indicating a parallel pulmonary and gastrointestinal (GI) absorption. A two-compartment disposition model with first order absorption from the GI and very rapid absorption from lungs (like an i.v. bolus) was found to describe successfully the C-t profiles of salmeterol. The estimated R value was 13% suggesting a high gut deposition of inhaled salmeterol. Women were found to exert less capability to eliminate salmeterol than men, while body weight (in allometric form) was found to be an important covariate on the peripheral volume of distribution.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetic analysis of inhaled salmeterol in asthma patients: Evidence from two dry powder inhalers

Soulele

Macheras

Karalis

2017

Biopharm & Drug Disp

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“…Salbutamol, a selective 132-adrenergic agonist, relaxes the bronchiolar smooth muscle within 5 rain of inhalation [1]. Pharmacokinetic studies have shown that inhaled salbutamol is absorbed to a considerable extent, leading to substantial systemic concentrations in the range of 1-5 ng/ml [34]. Peripheral MNC were chosen as a model to investigate the effect of salbutamol on the 13-adrenergic system in human airways, as both human MNC and human lung tissues have 132-adrenoceptors and because MNC are generally considered to appropriately reflect the 13-adrenergic status of other tissues [4,8,23,36].…”

Section: Discussionmentioning

confidence: 99%

Influence of short- and long-term inhalation of salbutamol on lung function and β2-andrenoceptors of mononuclear blood cells in asthmatic children

1991

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Clinical observations have shown that some asthma patients develop tachyphylaxis to beta-sympathomimetic drugs. As down-regulation of the number of beta-adrenoceptors in different human tissues after exposure to catecholamines and beta-adrenergic drugs is well known, we investigated whether a interrelation exists between beta-adrenoceptor down-regulation and clinically detectable beta-adrenergic subsensitivity during beta-sympathomimetic treatment. The following results were obtained: 1. beta 2-Sympathomimetic inhalation treatment with salbutamol in therapeutic doses led to a significant down-regulation of beta 2-adrenoceptors and consecutive cyclic adenosine monophosphate response to isoprenaline. This effect was already detectable after short-term treatment of 3-7 days in 9 asthmatic children. 2. In the long-term study over 6 months, salbutamol inhalation in 12 asthmatic children led to a significant down-regulation of beta-adrenoceptor binding sites on mononuclear blood cells (MNC) from 1539 +/- 91 to 1115 +/- 99 after 14 days, remaining in this range thereafter. 3. The mean airway resistance (Raw) of these 12 patients decreased significantly within 14 days from 8.1 +/- 0.8 to 5.7 +/- 0.5 cm H2O/l/s to remain stable throughout the 6 months of salbutamol treatment. The differences in Raw before and immediately after inhalation of 0.2 mg salbutamol (2 puffs) were unchanged during the study period. It is concluded, that long-term inhalative treatment with salbutamol over a period of 6 months does not result in refractoriness to beta-adrenergic drugs in the airways of asthmatic children, even though a significant down-regulation of beta 2-receptors on peripheral MNC occurs.

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“…This may affect the onset of action of the drug. Vaisman et al (1987) found that the bioavailability of inhaled salbutamol in 10 patients with cystic fibrosis was greater than that in healthy adults. These investigators postulated that the chronically diseased tracheobronchial tree in patients with cystic fibrosis results in higher permeability of salbutamol in this tissue.…”

Section: Pulmonary Deposition Of Inhaled Drugsmentioning

confidence: 94%

Pharmacokinetic Optimisation of Asthma Treatment

Taburet

Schmit

1994

Clinical Pharmacokinetics

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Asthma is generally managed with bronchodilator therapy and/or anti-inflammatory drugs. Guidelines now advocate selection of drugs and pharmaceutical formulations (long-acting vs short-acting, inhaled vs systemic) on the basis of disease severity. Theophylline has a narrow therapeutic margin. Clearance is highly variable and plasma concentrations should be monitored to avoid the occurrence of plasma concentration-related adverse effects. The rate of absorption of theophylline differs depending on the sustained release formulation administered. Some products do not provide sufficient plasma drug concentrations for therapeutic efficacy over a 12-hour period, particularly in patients with high clearance rates (e.g. children and patients who smoke). Administration of drugs via inhalation offers several advantages over systemic routes of administration (e.g. adverse effects are decreased). Inhalation is now advocated as first-line therapy. Aerosol medications available for the treatment of asthma are beta 2-agonist (including the newer long-acting agents such as salmeterol), corticosteroids, anticholinergic drugs, sodium cromoglycate (cromolyn sodium) and nedocromil. To reach the airways, aerosolised particles should be 1 to 5 microns in diameter. Particles of this size can be produced by nebuliser for continuous administration or by metered-dose inhaler and drug powder inhaler for unit dose medication. For efficient use of the metered-dose inhaler, slow inhalation and actuation must be coordinated. However, efficacy and convenience can be improved when spacer devices are used. Furthermore, spacer devices lessen the oropharyngeal adverse effects of inhaled corticosteroids. Dry powder inhalers are more easily used by children and elderly patients than metered-dose inhalers. Regardless of the device used, a maximum of 10% of the inhaled dose reaches the airways. The rest of the dose is swallowed and absorbed through the gastrointestinal tract. Most inhaled drugs have low oral bioavailability, either because of a high first-pass metabolism (beta 2-agonists and glucocorticoids) or because of lack of absorption (sodium cromoglycate). Sulphation of beta 2-agonists occurs in the wall of the gastrointestinal tract and extensive metabolism of inhaled corticosteroids occurs in the liver. Low bioavailability of the swallowed fraction contributes to reduced adverse effects. The pharmacokinetic properties of an inhaled drug are of interest. The fraction of the dose absorbed through the lung has the same disposition characteristics as an intravenous dose, and the swallowed fraction has the same disposition as an orally administered dose. However, for many drugs, pharmacokinetic data after inhalation are limited and cannot be used as a criteria for selection of therapy.(ABSTRACT TRUNCATED AT 400 WORDS)

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Pharmacokinetics of inhaled salbutamol in patients with cystic fibrosis versus healthy young adults

Cited by 22 publications

References 5 publications

Pharmacokinetic analysis of inhaled salmeterol in asthma patients: Evidence from two dry powder inhalers

Pharmacokinetic analysis of inhaled salmeterol in asthma patients: Evidence from two dry powder inhalers

Influence of short- and long-term inhalation of salbutamol on lung function and β2-andrenoceptors of mononuclear blood cells in asthmatic children

Pharmacokinetic Optimisation of Asthma Treatment

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