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Synthesis, Characterization, and In Vivo Evaluation of Desmethyl Anethole Trithione Phosphate Prodrug for Ameliorating Cerebral Ischemia-Reperfusion Injury in Rats
journal contribution
posted on 2020-02-24, 19:34 authored by Sheng Huang, Renhan Dong, Gaojie Xu, Jin Liu, Xiaofang Gao, Siqi Yu, Pengfan Qie, Gang Gou, Min Hu, Yu Wang, Jian Peng, Bing Guang, Ying Xu, Tai YangAnethol
trithione (ATT) has a wide range of physiological activities,
but its use is limited due to its poor water solubility. To improve
the solubility of ATT, we synthesized and characterized a novel phosphate
prodrug (ATXP) relying on the availability of the hydroxy group in
5-(4-hydroxyphenyl)-3H-1,2-dithiole3-thione (ATX),
which was transformed from ATT rapidly and extensively in vivo. Our
results showed that ATXP significantly improved drug solubility. ATXP
was rapidly converted to ATX and reached a maximum plasma concentration
with a Tmax of approximately 5 min after
intravenous (iv) administration. Furthermore, after the oral administration
of ATXP, the Cmax was 3326.30 ± 566.50
ng/mL, which was approximately 5-fold greater than that of the parent
drug form, indicating that ATXP has greater absorption than that of
ATT. Additionally, the oral phosphate prodrug ATXP increased the ATX
in the area under the plasma concentration vs time curves (AUC0–t = 3927.40 ± 321.50 and AUC0–∞ = 4579.0 ± 756.30), making its use in
practical applications more meaningful. Finally, compared to the vehicle,
ATXP was confirmed to maintain the bioactivity of the parent drug
for a significant reduction in infarct volume 24 h after reperfusion.
Based on these findings, the phosphate prodrug ATXP is a potentially
useful water-soluble prodrug with improved pharmacokinetic properties.
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plasma concentration vs time curvesT maxparent drug formwater solubilityC maxplasma concentrationRats Anethol trithionephosphate prodrug ATXPVivo EvaluationATTdrug solubilitynovel phosphate prodrugparent drugAUC5 minpharmacokinetic propertiesinfarct volume 24 hAmeliorating Cerebral Ischemia-Reperfusion Injuryhydroxy groupDesmethyl Anethole Trithione Phosphate Prodrug
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