Mukai H, Sugimoto T, Ago M, Morino A, Takaichi M, Ogawa Y, Seki H, Matsuura C, Esumi Y
Research Laboratories, Nippon Shinyaku Co., Ltd., Kyoto, Japan.
Arzneimittelforschung. 1999 Dec;49(12):977-85.
The tissue distribution and transfer into the fetus and milk of NS-105 ((+)-5-oxo-D-prolinepiperidinamide monohydrate, CAS 110958-19-5), a novel cognition enhancer, were investigated in rats after single oral administration of 14C-NS-105. The effects of repeated oral administration on the pharmacokinetics of NS-105 and hepatic drug-metabolizing enzyme activities also were investigated in rats. The radioactivity concentration in most tissues of male rats reached a maximum of 0.5 h after the single oral administration of 14C-NS-105, indicating rapid absorption and distribution, 0.5 h after the administration, the highest concentrations were present in the kidney and stomach, and the lowest in the white fat. The concentrations in the remaining tissues were moderately lower than the plasma value. The radioactivity concentrations in all the tissues tested decreased along with the plasma concentration, and were below or near the detection limit 24 h after the administration. Most of the radioactivity in the plasma, liver, kidney and cerebrum was due to unchanged NS-105. The tissue distribution patterns of radioactivity in female (non-pregnant) and pregnant rats after the oral administration of 14C-NS-105 did not differ from the pattern in male rats, revealing neither sex- nor pregnancy-related differences in NS-105 distribution. In pregnant rats, the maximum concentration in the fetus was 66% of that in the maternal plasma. In lactating rats, the radioactivity concentration in the milk was similar to that in the plasma. During and after the repeated oral administration of 14C-NS-105, the plasma concentrations and cumulative urinary and fecal excretions of radioactivity did not change with the number of administrations and were similar to the corresponding values after the single administration. The radioactivity concentrations in most tissues 8 h after the 7th, 14th and 21st administrations were about twice the corresponding values after the single administration, indicating that there is no marked accumulation of radioactivity in the tissues and that a steady state level was reached within 1 week. Repeated oral administration of NS-105 (10 mg/kg) to male rats did not affect hepatic drug-metabolizing enzyme activities.
在大鼠单次口服14C-NS-105后，研究了新型认知增强剂NS-105（(+)-5-氧代-D-脯氨酸哌啶酰胺一水合物，CAS 110958-19-5）在组织中的分布以及向胎儿和乳汁中的转移情况。还在大鼠中研究了重复口服给药对NS-105药代动力学和肝脏药物代谢酶活性的影响。雄性大鼠单次口服14C-NS-105后，大多数组织中的放射性浓度在给药后0.5小时达到最高值，表明吸收和分布迅速，给药后0.5小时，肾脏和胃中的浓度最高，白色脂肪中的浓度最低。其余组织中的浓度略低于血浆值。所有测试组织中的放射性浓度均随血浆浓度下降，给药后24小时低于或接近检测限。血浆、肝脏、肾脏和大脑中的大部分放射性是由于未变化的NS-105。雌性（未怀孕）和怀孕大鼠口服14C-NS-105后的放射性组织分布模式与雄性大鼠相同，表明NS-105分布不存在性别或怀孕相关差异。在怀孕大鼠中，胎儿中的最高浓度为母体血浆浓度的66%。在泌乳大鼠中，乳汁中的放射性浓度与血浆中的相似。在重复口服14C-NS-105期间及之后，血浆浓度以及放射性的累积尿排泄和粪排泄量不会随给药次数而变化，且与单次给药后的相应值相似。在第7次、第14次和第21次给药后8小时，大多数组织中的放射性浓度约为单次给药后相应值的两倍，表明组织中不存在明显的放射性蓄积，且在1周内达到稳态水平。对雄性大鼠重复口服NS-105（10 mg/kg）不会影响肝脏药物代谢酶活性。
