Shargel L, Dorrbecker S A
Drug Metab Dispos. 1976 Jan-Feb;4(1):72-8.
The metabolism and disposition of bitolterol, the di-p-toluate ester of N-t-butylarterenol (tBA) was studied in man after a single oral dose and in dog after intraduodenal, iv, or oral administration. The mean (+/- SE) peak plasma radioactivity in man (dose, 70 mug/kg) was 180 +/- 18 ng equivalents of [3H]bitolterol per ml or approximately 11% of the dose, whereas peak plasma radioactivity in dog (dose, 200 mug/kg) was 144 +/- 23 ng equivalents per ml or approximately 4% of the dose. For both man and dog, the time for maximum plasma level of radioactivity varied from 0.5 to 2 hr. In man, only 1% of the plasma radioactivity represented intact [3H]bitolterol 1.0 hr after medication. In the dog, radioactivity was concentrated in lung tissue after iv administration of [3H]bitolterol. Recovery of intact [3H]bitolterol in lung at 4.5 hr ranged from 26 to 46% of total tissue radioactivity after iv dosage and from 4 to 14% total tissue radioactivity after intraduodenal administration. Radioactivity recovered in human urine and feces (0-72 hr) accounted for 86 and 8.1% of the dose, respectively. Recovery of radioactivity in dog urine and feces accounted for 58 and 23% of the dose, respectively, in the same time period. Radiochromatograms of urine samples from man and dog revealed similar patterns of metabolites including free and conjugated forms of both tBA and the 3-O-methyl metabolite, N-t-butylmetarterenol. The major radioactive components of the feces were bitolterol and tBA. The results indicate that bitolterol is absorbed orally and retained as the intact ester in lung. The prolonged bronchodilator activity of bitolterol is due to the slow release of the ester from lung and hydrolysis to tBA, an active beta2-adrenoceptor agonist. Pharmacological activity is terminated by metabolism of tBA via conjugation or 3-O-methylation.
在单次口服给药后，对人以及十二指肠内给药、静脉注射或口服给药后的犬体内N-叔丁基肾上腺素（tBA）的二对甲苯酸酯——双甲苯喘定的代谢和处置情况进行了研究。人（剂量为70μg/kg）血浆放射性的平均（±标准误）峰值为每毫升180±18 ng当量的[³H]双甲苯喘定，约占剂量的11%，而犬（剂量为200μg/kg）血浆放射性峰值为每毫升144±23 ng当量，约占剂量的4%。对于人和犬而言，血浆放射性达到最高水平的时间在0.5至2小时之间。在人身上，用药1.0小时后，仅1%的血浆放射性代表完整的[³H]双甲苯喘定。在犬身上，静脉注射[³H]双甲苯喘定后，放射性集中在肺组织中。静脉给药后4.5小时，肺中完整的[³H]双甲苯喘定回收率在总组织放射性的26%至46%之间，十二指肠内给药后则在总组织放射性的4%至14%之间。人尿液和粪便（0至72小时）中回收的放射性分别占剂量的86%和8.1%。在同一时间段内，犬尿液和粪便中回收的放射性分别占剂量的58%和23%。人和犬尿液样本的放射色谱图显示出相似的代谢物模式，包括tBA和3-O-甲基代谢物N-叔丁基间羟异丙肾上腺素的游离和结合形式。粪便中的主要放射性成分是双甲苯喘定和tBA。结果表明，双甲苯喘定经口服吸收并以完整酯的形式保留在肺中。双甲苯喘定延长的支气管扩张活性归因于酯从肺中缓慢释放并水解为tBA，tBA是一种活性β₂肾上腺素能受体激动剂。药理活性通过tBA的结合或3-O-甲基化代谢而终止。
