title: Synthesis, radioprotective activity and pharmacokinetics characteristic of a new stable nitronyl nitroxyl radical-NIT2011.
abstract: A new stable nitronyl nitroxyl radical NIT2011 was synthesized and characterized. The radioprotective effect and pharmacokinetics profiles of NIT2011 were investigated. The results showed that when irradiation exposure dose was 6.5 Gy gama radiation, the survival rate in the irradiation-only group was 20% on 30th day. The survival rate was 70%, 80%, and 90% on 30th day when mice were pretreated with 0.25, 0.5 and 1.0 mmol/kg NIT2011, respectively. The pretreatment of NIT2011 increased number of spleen colonies, the numbers of bone marrow cells and protein level in bone marrow cells. Pretreatment with NIT2011 prior to radiation exposure increased the plasma SOD (superoxide dismutase) activity. 24 h after irradiation exposure, level of plasma MDA (malondialdehyde) in irradiation-only mice was 14.8 ± 2.8 nmol/mL, level of plasma MDA in NIT2011 (1 mmol/kg) pretreated mice was 9.8 ± 2.0 nmol/mL. Three days after irradiation exposure, the micronucleus ratio in irradiation-only mice is 40.2 ± 3.6, the micronucleus ratio in NIT2011 (1 mmol/kg) pretreated mice was 11.7 ± 1.2. NIT2011 was easily absorbed in mice after it was oral administrated. Compared with the intraperitoneal injection, the relative oral bioavailability of the NIT2011 was 27.5% in mice. The LD50 of NIT2011 was 1510 mg/kg in mice by oral administration. Thus, NIT2011 has potential in being developed as an oral dosage form, safe and effective radioprotective agent.
authors.affiliation: School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Haibo
authors.initials: H
authors.lastname: Wang
authors.forename: Yujing
authors.initials: Y
authors.lastname: Jia
authors.forename: Peng
authors.initials: P
authors.lastname: Gao
authors.forename: Ying
authors.initials: Y
authors.lastname: Cheng
authors.forename: Ming
authors.initials: M
authors.lastname: Cheng
authors.forename: Chentao
authors.initials: C
authors.lastname: Lu
authors.forename: Siyuan
authors.initials: S
authors.lastname: Zhou
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Sun
mesh_terms: D000284:Administration, Oral; D000818:Animals; D003497:Cyclic N-Oxides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D004307:Dose-Response Relationship, Radiation; D004355:Drug Stability; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000528:radiation effects; D048289:Imidazolidines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D011837:Radiation-Protective Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000378:metabolism; D014916:Whole-Body Irradiation
chemical_list: D003497:Cyclic N-Oxides; D048289:Imidazolidines; C585891:N-3'-nitrobenzoylpyrrolidinyl (4,4,5,5-tetramethylimidazoline-3-oxide-1-oxyl); D011837:Radiation-Protective Agents; D013482:Superoxide Dismutase