Adefovir Dipivoxyl 142340-99-6

Mechanism of action: adefovir is an acyclic nucleoside analogue of adenosine monophosphate, which is phosphorylated into an active metabolite, adefovir diphosphate, under the action of cell kinase. Adefovir diphosphate inhibits HBV DNA polymerase (reverse transcriptase) in the following two ways; One is to compete with the natural substrate deoxyadenosine triphosphate, and the other is to cause DNA strand elongation termination after integration into viral DNA. The inhibitory constant (Ki) of adefovir diphosphate on HBV DNA polymerase was 0.1 M.

Antiviral activity: in human hepatoma cell lines transfected with HBV, adefovir inhibits 50% viral DNA replication at concentrations ranging from 0.2 to 2.5uM (IC50).

Drug resistance: long-term drug resistance analysis (96-144 weeks) of patients receiving adefovir dipivoxil therapy who still had detectable serum HBV DNA was performed to determine whether the rtN236T and rtA181V variants were associated with adefovir resistance. In vitro studies found that rtN236T variation resulted in a 4-14 fold reduction in the sensitivity of HBV to adefovir, and a rebound in serum HBV DNA was observed in 6/6 patients with this variation. The rtA181V mutation reduced the sensitivity of HBV to adefovir by 2.5 to 3 times, and a rebound occurred in 2/3 of patients with this mutation. The incidence of ariations associated with adefouvir resistance was 0% (0/629) at 0-48 weeks, 2% (6/293) at 49-96 weeks, 1.8% (3/163) at 97-144 weeks, and 3.9% at 3 years.

Cross-drug resistance: the HBV mutant recombinant to lamivudine resistant-related mutations (rtL_180M, rtM204I, rtM204V, rtL180M + rtM204V, rtV173L) contained in the HBV DNA polymerase gene is sensitive to adefovir in vitro. Adefovir dipivoxil also showed an anti-hbv effect in patients with lamivudine resistance-associated variant HBV, with a median decrease in serum HBV DNA of 4.3 log10 copy number/ml. HBV variants containing DNA polymerase mutations (rtT128N and rtR153Q or rtW153Q, associated with hepatitis b immunoglobulin resistance) were sensitive to adefovir in vitro. In vitro studies showed that HBV with the rtN236T mutation associated with adefovir resistance was 2 to 3 times less sensitive to lamivudine, while HBV with the rtA181V mutation associated with adefovir resistance was 3 times less sensitive to lamivudine.