Makovec F, Chisté R, Peris W, Setnikar I
Rotta Research Laboratorium, Monza/Milano, Italy.
Arzneimittelforschung. 1987 Jul;37(7):806-13.
The pharmacokinetics and metabolism of 1H-indole-3-acetic acid, 1-(4-chlorobenzoyl)-5-methoxy-2-methyl 2-[4-[3-[[4-(benzoylamino)-5-(dipropylamino)-1, 5-dioxopentyl]oxy]propyl]-1-piperazinyl]ethyl ester (+/-) (proglumetacin, CR 604), 14C-labelled in position C-2 of the indolic moiety, was studied in male and female rats after oral administration. The radioactivity is slowly absorbed from the gastrointestinal tract and reaches the peak in plasma 6 h after administration. Afterwards the radioactivity is eliminated from plasma according to a bi-exponential equation, with an initial elimination rate having a t1/2 of 4.5 h and a terminal elimination rate having a t1/2 of 16 h. The elimination rate is probably dependent on the slow absorption rate (flip-flop system) and on an entero-hepatic recirculation of the radioactivity. The radioactivity is excreted with the feces (60.8%) and with the urines (33.5%). No radioactivity is eliminated with the expired air. About 13% of the fecal radioactivity is represented by proglumetacin. This fraction or radioactivity (ca. 8% of the administered) represents probably the non-absorbed amount of substance. The parent proglumetacin is not found in blood, urine and organs. Conversely several indolic metabolites are found, with a predomination of indometacin. Proglumetacin is therefore a pro-drug of indometacin and of other indolic metabolites, which are responsible for the antiinflammatory activity of proglumetacin. The radioactivity is distributed in all tissues. The maximum radioactivity is found in liver and kidneys, however, always in a smaller concentration than in plasma. No "deep compartment" was found.
对1H-吲哚-3-乙酸、1-(4-氯苯甲酰基)-5-甲氧基-2-甲基2-[4-[3-[[4-(苯甲酰氨基)-5-(二丙基氨基)-1,5-二氧代戊基]氧基]丙基]-1-哌嗪基]乙酯(±)(丙谷美辛，CR 604，吲哚部分的C-2位用14C标记)在雄性和雌性大鼠口服给药后的药代动力学和代谢情况进行了研究。放射性物质从胃肠道缓慢吸收，给药后6小时在血浆中达到峰值。此后，血浆中的放射性物质根据双指数方程消除，初始消除速率的t1/2为4.5小时，终末消除速率的t1/2为16小时。消除速率可能取决于缓慢的吸收速率(翻转系统)和放射性物质的肠肝循环。放射性物质通过粪便(60.8%)和尿液(33.5%)排出。呼出气体中未检测到放射性物质。粪便中的放射性物质约13%由丙谷美辛代表。该部分放射性物质(约占给药量的8%)可能代表未吸收的物质。在血液、尿液和器官中未发现母体丙谷美辛。相反，发现了几种吲哚代谢物，其中吲哚美辛占主导。因此，丙谷美辛是吲哚美辛和其他吲哚代谢物的前体药物，这些代谢物负责丙谷美辛的抗炎活性。放射性物质分布于所有组织中。肝脏和肾脏中的放射性物质最多，但浓度始终低于血浆。未发现“深部隔室”。
