Pharmacokinetics and excretion of unique beta-adrenergic agonists.
Pharmacokinetics and excretion of unique beta-adrenergic agonists.
复制标题
独特的β-肾上腺素能激动剂的药代动力学和排泄。
DOI：
10.1159/000138265
复制
发表时间：
1987
期刊：
影响因子：
3.1
通讯作者：
CastagnoliJr,N
中科院分区：
文献类型：
--
作者：
Ferraiolo,BL;Halldin,MM;Asscher,Y;Akita,Y;Melmon,KL;Benet,LZ;CastagnoliJr,N
研究了异丙肾上腺素的β-肾上腺素能激动剂类似物（同源物）在大鼠中的血浆药代动力学特征以及胆汁和尿液消除特征，其中N-异丙基通过四碳亚甲基间隔基与α-甲基-（119）或β-三氟甲基-（143）苯胺部分连接。尽管这些独特的β-肾上腺素能激动剂和异丙肾上腺素之间的药理学作用选择性和作用持续时间存在差异，但静脉给药后，未观察到其血浆药代动力学参数存在差异。血浆清除迅速（67-78 ml/min），化合物分布广泛。与已知的异丙肾上腺素消除特征相反，胆汁排泄是119和143消除的主要途径。静脉注射119和143的大鼠胆汁HPLC色谱图中出现母体药物和“一个”主要代谢物峰。初步证据表明，该代谢产物峰由一个或多个葡糖苷酸和/或硫酸盐结合物组成。尿排泄对119和143的定量重要性似乎低于异丙肾上腺素。衍生物在心脏中的滞留时间延长可能有助于解释这些独特的β-肾上腺素能激动剂的异常作用和组织特异性药理学特性。
β-Adrenergic agonist analogs (congeners) of isoproterenol in which the N-isopropyl group has been linked to ap-methyl-(119)orp-trifluoromethyl-(143)anilide moiety through a four carbon methylene spacer have been investigated with respect to their plasma pharmacokinetic profiles and biliary and urinary elimination characteristics in rats. In spite of the differences in selectivity of pharmacologic effects and durations of action between these unique β-adrenergic agonists and isoproterenol, no differences were observed in their pharmacokinetic parameters in plasma after intravenous administration. Plasma clearances were rapid (67–78 ml/min) and the compounds were widely distributed. In contrast to the known elimination characteristics of isoproterenol, biliary excretion was the major pathway for elimination of119and143.Parent drug and ‘one’ major metabolite peak appeared in HPLC chromatograms of bile collected from rats that received119and143by intravenous administration. Preliminary evidence suggests that this metabolite peak consists of one or more glucuronide and/or sulfate conjugates. Urinary excretion appears to be of lesser quantitative importance for119and143than for isoproterenol. The protracted duration of residence of the derivatives in the heart may help to explain the unusual effects and tissue-specific pharmacological properties of these unique β-adrenergic agonists.