Pharmacological effects of entecavir

Microbiological mechanisms of action
This product is a guanine nucleoside analog, which has an inhibitory effect on hepatitis B virus (HBV) polymerase. It can become an active triphosphate through phosphorylation, and the half-life of triphosphate in cells is 15 hours. By competing with the natural substrate of HBV polymerase, deoxyguanine triphosphate nucleoside, entecavir triphosphate can inhibit all three activities of viral polymerase (reverse transcriptase): (1) the activation of HBV polymerase; (2) Formation of reverse transcriptional negative chains of pre genomic mRNA; (3) Synthesis of HBV DNA positive strand. The inhibitory constant (Ki) of entecavir triphosphate on HBV DNA polymerase is 0.0012 μ M. The effect of entecavir triphosphate on cells α、β、δ DNA polymerase and mitochondria γ The inhibitory effect of DNA polymerase is weak, with Ki values ranging from 18 to 160 μ M.
Antiviral activity
In human HepG2 cells transfected with wild type hepatitis B virus, the concentration (EC50) required for entecavir to inhibit 50% viral DNA synthesis is 0.004 μ M. The median EC50 of entecavir against lamivudine resistant virus strains (rtL180M, rtM204V) is 0.026 μ M (range 0.01 to 0.059 μ M) However, entecavir has no clinically relevant activity against human immunodeficiency virus type 1 (HIV) grown in cell culture medium (EC50] 10 μ M) .
Daily or weekly use of this product can reduce hepatitis virus DNA levels in North American marmots and ducks (4 to 8 log10). Long term studies on five North American marmots have shown that oral administration of 0.5mg/kg entecavir (equivalent to a dose of 1.0mg in humans) per week can maintain the viral DNA of three of them at undetectable levels (viral DNA levels [200 copies/mL, PCR method) for up to three years. No changes in HBV polymerase related to entecavir resistance were found in any animal treated with this drug for up to three years.
In vitro study of drug resistance
In cell experiments, it was found that the phenotypic sensitivity of lamivudine resistant virus strains to entecavir decreased by 8 to 30 times. If there is amino acid substitution (rtL180M and/or rtM204V/I) for lamivudine resistance of hepatitis B virus polymerase, plus the substitution mutation of rtT184, rtS202 or rtM250, or on the basis of the simultaneous occurrence of the above two mutations, regardless of the substitution mutation of rtI169, the phenotype sensitivity of entecavir will be reduced more (] 70 times).