The need for medical radiation countermeasures is ever increasing. Yet, safe and effective radio-protectors are not available. ?-Tocotrienol (DT3) has showed promising radio-protective effect in animal studies. However, the poor pharmacokinetics (PK) of DT3 may diminish its potential use as a radio-protector.
To discover new DT3-based radio-protectors with improved PK profiles and/or potency, we applied various structural modification strategies to design and synthesize DT3 analogues. DT3-F2, d6-DT3, XL13511, and XL34604B were designed in attempts to slow down the ω-hydroxylation of the farnesyl side chain of DT3 and thus to improve metabolic stability and bioavailability. δ-Tocodienol was designed to increase the binding affinity to a-tocopherol transfer protein (a-TTP). With extensive synthetic work, these DT3 analogues were obtained successfully.
An in vitro metabolic stability assay using mouse liver microsomes identified d6-DT3, which had a 32% increase in metabolic stability compared with DT3 and was the most stable DT3 analogue in this assay. In addition, anti-oxidative and anti-inflammatory effects of d6-DT3 were comparable to DT3 in various cell-based assays.
In mouse survival studies, a single subcutaneous (SC) injection (200 mg/Kg) of DT3 or d6-DT3 24 h before receiving lethal doses of total body γ-irradiation significantly increased survival rate. A side by side comparison between DT3 and d6-DT3 using various doses found that they had comparable radio-protective effect. d6-DT3 treatment afforded 50%, 87.5%, and 100% survival rate at 50 mg/kg, 100 mg/kg, and 200 mg/kg doses, respectively, while DT3 treatment afforded 37.5%, 87.5%, and 75% survival rate at the same corresponding doses. d6-DT3 also showed comparable PK profiles (intravenous, 50 mg/Kg, mouse, n = 4) compared with DT3 as indicated by their similar plasma concentrations, clearances (1.400 L*Kg-1*h -1 vs 1.495 L*Kg-1*h-1) and Ke values (0.0656 h-1 vs 0.0721 h-1), and bioavailability values (8.30% vs 7.86%).
SC injection (200 mg/Kg dose) of DT3 and d6-DT3 in mice induced high levels of plasma G-CSF, which is believed to be responsible for their radio-protective effects. Using an in vivo G-CSF induction assay of DT3 analogues, we identified Suc-DT3 as the most potent G-CSF inducer, which deserves further studies.
|Commitee:||Crooks, Peter A., Crow, John P., Hendrickson, Howard P., Zhou, Daohong|
|School:||University of Arkansas for Medical Sciences|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 79/10(E), Dissertation Abstracts International|
|Keywords:||Delta-tocotrienol, G-csf, Ionizing radiation, Pharmacokinetics, Radio-protector, Vitamin e|
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