Wang S X, Sutfin T A, Bäärnhielm C, Regårdh C G
Hässle Cardiovascular Research Laboratories, Mölndal, Sweden.
J Pharmacol Exp Ther. 1989 Aug;250(2):632-6.
The systemic availability of intraduodenally (i.d.) administered felodipine in the rat is about 10%. The purpose of this study was to determine to what extent intestinal metabolism contributes to the first-pass elimination of felodipine in the rat. Four different types of experiments were performed. 1) [3H]Felodipine was given i.v. and i.p.; 2) the uptake of i.p. administered [3H]felodipine by the lymph was studied for 3 hr after dosing; 3) portal blood was collected quantitatively for 40 min after i.d. administration of [3H]felodipine; and 4) the in vitro metabolism of felodipine was studied in intestinal cell suspensions. The mean bioavailability of the i.p. dose was approximately 48%. The uptake via the lymph was negligible as an insignificant amount of the radioactive i.p. dose was recovered in lymph from a main lymph vessel in the peritoneal cavity. An average of 21 +/- 12% of given radioactive dose was recovered in portal blood during the first 40 min after i.d. dosing. The recovered radioactivity was to 40 to 70% due to felodipine and 9 to 16% was due to dehydro-felodipine. These results indicate that substantial first-pass elimination occurs in the intestine of the rat. Further support for gastrointestinal metabolism of felodipine in the rat was obtained from incubations with intestinal cells.
大鼠十二指肠内给予非洛地平后的系统利用率约为10%。本研究的目的是确定肠道代谢在多大程度上导致大鼠非洛地平的首过消除。进行了四种不同类型的实验。1）静脉注射和腹腔注射[3H]非洛地平；2）给药后3小时研究腹腔注射[3H]非洛地平的淋巴摄取情况；3）十二指肠内给予[3H]非洛地平后40分钟定量收集门静脉血；4）在肠细胞悬液中研究非洛地平的体外代谢。腹腔注射剂量的平均生物利用度约为48%。由于从腹腔主要淋巴管的淋巴中回收的放射性腹腔注射剂量微不足道，因此通过淋巴的摄取可忽略不计。十二指肠内给药后最初40分钟内，门静脉血中平均回收了21±12%的给药放射性剂量。回收的放射性物质中，40%至70%归因于非洛地平，9%至16%归因于脱氢非洛地平。这些结果表明，大鼠肠道中发生了大量的首过消除。用肠细胞进行孵育进一步支持了大鼠非洛地平的胃肠道代谢。
