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Eur J Pharm Sci. 2012 Jan 23;45(1-2):110-5. doi: 10.1016/j.ejps.2011.10.028. Epub 2011 Nov 9.

Synthesis, stability and pharmacological evaluation of a novel codrug consisting of lamivudine and ursolic acid.

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1
School of Chemistry and Chemical Engineering, Southeast University, Nanjing 210096, PR China.

Abstract

A novel codrug (LMX) was obtained from lamivudine (LMV) and ursolic acid (UA) coupled with ethyl chloroacetate through an amide and ester linkage. The structure of LMX was confirmed by ¹H NMR, ¹³C NMR, IR and HRMS. Herein, the in vitro non-enzymatic and enzymatic hydrolysis and in vivo pharmacological activities of LMX were studied. The kinetics of hydrolysis of LMX was studied in aqueous solution of pH 1-10, 80% buffered human plasma and in the presence of lipase from Porcine pancreas (EC 3.1.1.3) at 37°C. It is found that LMX hydrolysis rate was significantly faster in lipase with half-life of 1.4h compared to pH 7.4 phosphate buffer (t(1/2) 11.2h) and buffered human plasma (t(1/2) 5.4h). The decomposition rates in aqueous solution (pH 1-10) showed a U-shaped curve. LMX was comparatively stable between pH 3 and 6 (half-life >40 h). Pharmacological studies indicated that LMX had the dual action of anti-hepatitis B virus activity and hepatoprotective effects against acute liver injury. These findings suggest that LMX could be a promising candidate agent for the treatment of hepatitis.

PMID:
22085635
DOI:
10.1016/j.ejps.2011.10.028
[Indexed for MEDLINE]
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