Sugimoto T, Hayashi T, Okita A, Morino A
Research Laboratories, Nippon Shinyaku Co., Ltd., Kyoto, Japan.
Arzneimittelforschung. 1996 Feb;46(2):114-27.
Pharmacokinetics of 14C-labeled montirelin hydrate (CAS 90243-66-6, NS-3) in rats was studied after single or repeated intravenous administration. 1. Radioactivity concentrations in tissues after single administration to male and female rats were highest in the kidney followed (in this order) by plasma, liver, blood, pancreas, uterus (female rats), lung and skin and low in various brain sites 5 min after administration. The concentrations in most tissues were practically parallel to those in plasma over the 24-h period after administration. After decreasing rapidly the concentrations rose slightly for 10 h and then decreased gradually. 2. Five min after single administration to male rats, the concentration of the main metabolite CNK-6004 (deamidated product) was lower in the plasma, but higher in the liver and kidney than the NS-3 concentration. From 0.5 to 2 h after administration, the concentration of CNK-6004 was higher than that of NS-3 in the plasma, liver and kidney, accounting for 33-64% of the radioactivity concentration. 3. After administration to rats on the 18th day of pregnancy, the radioactivity concentrations in the fetal whole body and fetal tissues peaked later than those in the maternal plasma, tissues and placenta. The maximum concentration in the fetal tissues was 2% or less of that in the maternal plasma. 4. After administration to lactating rats, the radioactivity concentration in milk reached the maximum 10 h after administration, and decreased gradually in parallel with the concentration in the plasma 24 to 168 h after administration. 5. During repeated once daily administration for 10 days, the radioactivity concentration in the plasma 24 h after each administration reached practically steady state level after the 7th administration and decreased with a half-life of 38.1 h after the last administration. 6. The radioactivity concentrations in most tissues after the last administration were not significantly different from those after a single administration. Decreased elimination of the radioactivity was observed in the white fat and skin, in which radioactivity levels were higher than those in the other tissues a long time after the last dose. 7. Excretion of the radioactivity in the urine and feces during repeated administration was constant after the 2nd administration. The excretion by 168 h after the last administration was 66.9 and 14.3% of the cumulative dose in the urine and feces, respectively (total: 81.2%). 8. The composition of metabolites in the plasma, liver, kidney and urine after the last administration did not differ markedly from that after a single administration. Once daily repeated administration for 7 days had no effect on the liver drug metabolizing enzyme activities.
在大鼠单次或多次静脉给药后，研究了14C标记的水合孟替瑞林（CAS 90243-66-6，NS-3）的药代动力学。1. 对雄性和雌性大鼠单次给药后5分钟，各组织中的放射性浓度以肾脏最高，其次（按此顺序）为血浆、肝脏、血液、胰腺、子宫（雌性大鼠）、肺和皮肤，而在各个脑区较低。给药后24小时内，大多数组织中的浓度与血浆中的浓度实际呈平行关系。浓度在迅速下降后，先轻微上升10小时，然后逐渐下降。2. 对雄性大鼠单次给药后5分钟，主要代谢物CNK-6004（脱酰胺产物）在血浆中的浓度较低，但在肝脏和肾脏中的浓度高于NS-3的浓度。给药后0.5至2小时，CNK-6004在血浆、肝脏和肾脏中的浓度高于NS-3，占放射性浓度的33%-64%。3. 在妊娠第18天对大鼠给药后，胎儿全身和胎儿组织中的放射性浓度达到峰值的时间晚于母体血浆、组织和胎盘。胎儿组织中的最大浓度为母体血浆中最大浓度的2%或更低。4. 对哺乳期大鼠给药后，乳汁中的放射性浓度在给药后10小时达到最高，并在给药后24至168小时与血浆中的浓度平行逐渐下降。5. 在连续10天每日给药一次的过程中，每次给药后24小时血浆中的放射性浓度在第7次给药后实际达到稳态水平，并在最后一次给药后以38.1小时的半衰期下降。6. 最后一次给药后，大多数组织中的放射性浓度与单次给药后无显著差异。在白色脂肪和皮肤中观察到放射性消除减少，在最后一次给药后很长一段时间内，这些组织中的放射性水平高于其他组织。7. 在重复给药期间，第2次给药后尿液和粪便中的放射性排泄量保持恒定。最后一次给药后168小时，尿液和粪便中的排泄量分别为累积剂量的66.9%和14.3%（总计：81.2%）。8. 最后一次给药后血浆、肝脏、肾脏和尿液中代谢物的组成与单次给药后无明显差异。连续7天每日重复给药对肝脏药物代谢酶活性无影响。
