新型支气管扩张剂富马酸福莫特罗在大鼠和犬体内的处置与代谢

Disposition and metabolism of formoterol fumarate, a new bronchodilator, in rats and dogs.

Sasaki H, Kamimura H, Shiobara Y, Esumi Y, Takaichi M, Yokoshima T

Xenobiotica. 1982 Dec;12(12):803-12. doi: 10.3109/00498258209038952.

Abstract

The disposition and metabolism of formoterol fumarate, a highly potent beta 2-adrenoceptor stimulant, were studied in rats and dogs. 2. After oral administration of [3H] formoterol fumarate to dogs, unchanged formoterol accounted for greater than 60% of the plasma radioactivity immediately after dosage; greater than 20% was due to the unchanged drug until 12 h after dosage. In contrast, only 1-3% of the radioactivity was present as unchanged drug in rat plasma. After i.v. dosage, unchanged drug was much higher in both species. The elimination half-life of formoterol was 4-6 h in dogs and 1.7 h in rats. 3. In both species, 36-45% of the dose was excreted in urine and 50-56% in faeces in 72 h, irrespective of the administration route. Biliary excretion after oral dosage amounted to 65 and 31% in rats and dogs, respectively. 4. T.l.c. before and after enzymic hydrolysis revealed that the drug was excreted in urine and bile of rats mostly as a conjugate. Dog urine also contained the conjugate but the unchanged drug was much higher than in rats. The conjugated metabolite was purified from rat urine and identified as the 2-O-glucuronide. The glucuronide was the only metabolite detected in the urine and bile of rats and in the urine of dogs.

摘要

对高效β2 -肾上腺素受体激动剂富马酸福莫特罗在大鼠和犬体内的处置和代谢进行了研究。2. 给犬口服[3H]富马酸福莫特罗后，给药后即刻血浆放射性中未变化的福莫特罗占比超过60%；给药后12小时内，超过20%是由于未变化的药物所致。相比之下，大鼠血浆中以未变化药物形式存在的放射性仅为1 - 3%。静脉给药后，两种动物体内未变化的药物含量都高得多。福莫特罗在犬体内的消除半衰期为4 - 6小时，在大鼠体内为1.7小时。3. 在两种动物中，无论给药途径如何，72小时内36 - 45%的剂量经尿液排泄，50 - 56%经粪便排泄。口服给药后，大鼠和犬的胆汁排泄量分别为65%和31%。4. 酶解前后的薄层色谱显示，该药物在大鼠尿液和胆汁中大多以结合物形式排泄。犬尿液中也含有结合物，但未变化的药物比大鼠尿液中的含量高得多。从大鼠尿液中纯化出结合代谢物并鉴定为2 - O -葡萄糖醛酸苷。葡萄糖醛酸苷是在大鼠尿液和胆汁以及犬尿液中检测到的唯一代谢物。