title: Oral biological activities of spontaneous nitric oxide releasers are accounted for by their nitric oxide-releasing rates and oral absorption manners.
abstract: 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.
authors.affiliation: New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kita
authors.forename: Y
authors.initials: Y
authors.lastname: Hirasawa
authors.forename: S
authors.initials: S
authors.lastname: Fukuyama
authors.forename: K
authors.initials: K
authors.lastname: Ohkubo
authors.forename: Y
authors.initials: Y
authors.lastname: Kato
authors.forename: H
authors.initials: H
authors.lastname: Takamatsu
authors.forename: M
authors.initials: M
authors.lastname: Ohno
authors.forename: S
authors.initials: S
authors.lastname: Nishino
authors.forename: M
authors.initials: M
authors.lastname: Kato
authors.forename: J
authors.initials: J
authors.lastname: Seki
mesh_terms: D000042:Absorption; D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009539:Nicotinic Acids / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D009574:Nitro Compounds / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: C094368:FR 144420; D009539:Nicotinic Acids; D009574:Nitro Compounds; D014665:Vasodilator Agents; D009569:Nitric Oxide; C061872:FK 409