Using Salt Counterions to Modify β2-Agonist Behavior in Vivo
Using Salt Counterions to Modify β2-Agonist Behavior in Vivo
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DOI：
10.1021/acs.molpharmaceut.6b00448
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发表时间：
2016-10-01
影响因子：
4.9
通讯作者：
Page, Clive P.
中科院分区：
文献类型：
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作者：
Patel, Aateka;Keir, Sandra D.;Page, Clive P.
描述盐反离子对吸入药物在体内生物学性能的影响的数据很少。本研究的目的是确定联合应用盐反离子是否影响沙丁胺醇、福莫特罗和沙美特罗的组织通透性和气道平滑肌松弛能力。结果表明，只有沙丁胺醇与过量的1-羟基-2-萘甲酸酯(1H2NA)对抗离子配制时，表现出比沙丁胺醇碱更好的支气管扩张作用(p<；0.05)。天冬氨酸、马来酸、富马酸和1H_2NA不影响福莫特罗或沙美特罗降低体内气道阻力的能力。使用豚鼠气管切片的研究表明，与沙丁胺醇基质相比，沙丁胺醇：1H2NA的组合导致了显著更快的组织传输速度(p<；0.05)。此外，用电刺激的豚鼠气管灌流标本在体外评价沙丁胺醇的松弛活性时，沙丁胺醇在1H_2NA存在下对收缩的抑制作用大于沙丁胺醇基质(总抑制率为94.13%，p<；0.05)。给药后沙丁胺醇的行为发生改变的原因被认为是离子对的形成，并用红外光谱进行了鉴定。离子对的形成可以改变药物的物理化学性质，这项研究的数据表明，吸入药物盐中反离子的选择应该仔细考虑，好像有可能改变药物在体内的作用。
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 if has the potential to alter drug action in vivo.