title: Using Salt Counterions to Modify β2-Agonist Behavior in Vivo.
abstract: There is a paucity of data describing the impact of salt counterions on the biological performance of inhaled medicines in vivo. The aim of this study was to determine if the coadministration of salt counterions influenced the tissue permeability and airway smooth muscle relaxation potential of salbutamol, formoterol, and salmeterol. The results demonstrated that only salbutamol, when formulated with an excess of the 1-hydroxy-2-naphthoate (1H2NA) counterion, exhibited a superior bronchodilator effect (p < 0.05) compared to salbutamol base. The counterions aspartate, maleate, fumarate, and 1H2NA had no effect on the ability of formoterol or salmeterol to reduce airway resistance in vivo. Studies using guinea pig tracheal sections showed that the salbutamol:1H2NA combination resulted in a significantly faster (p < 0.05) rate of tissue transport compared to salbutamol base. Furthermore, when the relaxant activity of salbutamol was assessed in vitro using electrically stimulated, superfused preparations of guinea pig trachea, the inhibition of contraction by salbutamol in the presence of 1H2NA was greater than with salbutamol base (a total inhibition of 94.13%, p < 0.05). The reason for the modification of salbutamol's behavior upon administration with 1H2NA was assigned to ion-pair formation, which was identified using infrared spectroscopy. Ion-pair formation is known to modify a drug's physicochemical properties, and the data from this study suggested that the choice of counterion in inhaled pharmaceutical salts should be considered carefully as it has the potential to alter drug action in vivo.
authors: Sackler Institute of Pulmonary Pharmacology, Faculty of Life Sciences & Medicine, King's College London , 150 Stamford Street, London SE1 9NH, U.K.|Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London , 150 Stamford Street, London SE1 9NH, U.K.
authors: Aateka
authors: A
authors: Patel
authors: Sackler Institute of Pulmonary Pharmacology, Faculty of Life Sciences & Medicine, King's College London , 150 Stamford Street, London SE1 9NH, U.K.|Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London , 150 Stamford Street, London SE1 9NH, U.K.
authors: Sandra D
authors: SD
authors: Keir
authors: MedPharm Ltd , Units 1 and 3, Chancellor Court, 50 Occam Road, Surrey Science Park, Guildford, Surrey GU2 7AB, U.K.|School of Pharmacy, University of Hertfordshire , College Lane, Hatfield, Hertfordshire AL10 9AB, U.K.
authors: Marc B
authors: MB
authors: Brown
authors: Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London , 150 Stamford Street, London SE1 9NH, U.K.
authors: Robert
authors: R
authors: Hider
authors: Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London , 150 Stamford Street, London SE1 9NH, U.K.
authors: Stuart A
authors: SA
authors: Jones
authors: Sackler Institute of Pulmonary Pharmacology, Faculty of Life Sciences & Medicine, King's College London , 150 Stamford Street, London SE1 9NH, U.K.|Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London , 150 Stamford Street, London SE1 9NH, U.K.
authors: Clive P
authors: CP
authors: Page
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000737:chemistry* / Q000494:pharmacology*; D000420:Albuterol / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001224:Aspartic Acid; D002851:Chromatography, High Pressure Liquid; D004339:Drug Compounding; D005650:Fumarates / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D008298:Maleates / Q000378:metabolism; D009284:Naphthols / Q000737:chemistry*; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D005650:Fumarates; D008298:Maleates; D009284:Naphthols; D001224:Aspartic Acid; C030272:maleic acid; D000420:Albuterol; C050175:1-hydroxy-2-naphthoic acid
keywords: 1H2NA; airways; counterion; ion-pair; pharmaceutical salt; salbutamol