Kita Y, Hirasawa Y, Fukuyama S, Ohkubo K, Kato Y, Takamatsu H, Ohno M, Nishino S, Kato M, Seki J
New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
J Pharmacol Exp Ther. 1996 Feb;276(2):421-5.
We examined whether p.o. biological activities of (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (FK409), a spontaneous nitric oxide (NO) releaser, and the derivatives, i.e., (+/-)-[(E)-4-ethyl-3-[(Z)-hydroxyimino]-5-nitro-3-hexenyl]-3 - pyridinecarboxamide (FR144420) and (+/-)-N-[(E)-4-ethyl-3-[(Z)-hydroxyimino]-6-methyl-5- nitro-3-heptenyl]-3-pyridinecarboxamide (FR146801), could be accounted for by their NO-releasing rates and p.o. absorption manners. These compounds spontaneously released NO with the rates in the rank order of FK409 > FR144420 > FR146801. Total contribution of these drugs as NO donors in vivo was almost the same from the determination of urinary nitrite/nitrate (NOx) levels after p.o. administration of the compounds at 10 mg/kg to rats. Plasma NOx level after p.o. administration of FK409 at 10 mg/kg to rats reached maximal level at 120 min, and decreased gradually. On the other hand, plasma NOx levels time-dependently increased during 360 min after p.o. administration of FR144420 and FR146801 at the same dose. FK409 and FR144420 showed hypotensive effects immediately after p.o. administration at 10 mg/kg to rats, and the maximum response of FR144420 was less and the duration of the effect was longer than those of FK409, respectively. On the other hand, FR146801, which is most stable in solution, did not show any significant hypotensive effect during 240 min after p.o. administration at the same dose. In conclusion, the response and the duration of biological activity after p.o. administration of three spontaneous NO releasers can be closely accounted for by their NO-releasing rates and p.o. absorption manners.
我们研究了自发释放一氧化氮（NO）的化合物（±）-（E）-4-乙基-2-[(E)-羟基亚氨基]-5-硝基-3-己烯酰胺（FK409）及其衍生物，即（±）-[(E)-4-乙基-3-[(Z)-羟基亚氨基]-5-硝基-3-己烯基]-3-吡啶甲酰胺（FR144420）和（±）-N-[(E)-4-乙基-3-[(Z)-羟基亚氨基]-6-甲基-5-硝基-3-庚烯基]-3-吡啶甲酰胺（FR146801）经口服后的生物学活性是否可由其NO释放速率和口服吸收方式来解释。这些化合物自发释放NO的速率顺序为FK409 > FR144420 > FR146801。通过测定化合物以10 mg/kg口服给予大鼠后的尿中亚硝酸盐/硝酸盐（NOx）水平，发现这些药物作为体内NO供体的总贡献几乎相同。以10 mg/kg口服给予大鼠FK409后，血浆NOx水平在120分钟时达到最高水平，然后逐渐下降。另一方面，以相同剂量口服给予FR144420和FR146801后，血浆NOx水平在360分钟内随时间增加。FK409和FR144420以10 mg/kg口服给予大鼠后立即显示出降压作用，并且FR144420的最大反应较小，作用持续时间比FK409长。另一方面，在溶液中最稳定的FR146801以相同剂量口服给药后240分钟内未显示出任何显著的降压作用。总之，三种自发NO释放剂口服给药后的反应和生物活性持续时间可由其NO释放速率和口服吸收方式密切解释。
