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HomeProduct name listAdefovir dipivoxil

Adefovir dipivoxil

Synonym(s):9-(2[bis(Pivaloyloxymethoxy)phosphorylmethoxy]ethyl)adenine

  • CAS NO.:142340-99-6
  • Empirical Formula: C20H32N5O8P
  • Molecular Weight: 501.47
  • MDL number: MFCD00869897
  • EINECS: 200-001-8
  • SAFETY DATA SHEET (SDS)
  • Update Date: 2024-11-19 23:02:33
Adefovir dipivoxil Structural

What is Adefovir dipivoxil?

Absorption

The approximate oral bioavailability of adefovir from HEPSERA is 59%. When a single oral 10 mg dose is given to chronic hepatitis B patients, the peak plasma concentration (Cmax) of adefovir was 18.4 ± 6.26 ng/mL. This occurred between 0.58 - 4 hours post dose (Tmax). The adefovir area under the plasma concentration-time curve (AUC0–∞) was 220 ± 70.0 ng?h/mL. Food does not affect the exposure of adeforvir.

Toxicity

Renal tubular nephropathy characterized by histological alterations and/or increases in BUN and serum creatinine was the primary dose-limiting toxicity associated with administration of adefovir dipivoxil in animals. Nephrotoxicity was observed in animals at systemic exposures approximately 3–10 times higher than those in humans at the recommended therapeutic dose of 10 mg/day.

Description

Adefovir dipivoxil is the first nucleotide analog to be launched in the US as an oral treatment for hepatitis B virus (HBV) infections. It can be easily prepared in 4 steps from adenine. Adefovir dipivoxil acts as a bioavailable ester prodrug which is rapidly hydrolyzed to free adefovir and further anabolized to its active form, adefovir diphosphate, by two intracellular phosphotylation steps. The diphosphate competitively inhibits reverse transcriptase and/or causes chain termination when incorporated into growing DNA. Adefovir dipivoxil has a broad antiviral spectrum against retro-, herpes- and hepadnaviruses. The drug inhibits HBV replication, decreases HBV DNA levels and improves liver histology of patients infected with HBV wild type and resistant to other antivirals such as lamivudine. It also demonstrated activity in hepatitis B”e” antigennegative, or precore mutant, patients and in patients co-infected with HIV. To date, no adefovir dipivoxil-associated resistance mutations have been identified in patients up to 136 weeks with the drug. The oral bioavailability of adefovir after oral administration of its dipivoxil prodrug is approximately 30%. It is mainly excreted unchanged in the urine and its plasma elimination half-life is 4.2 h. However, a long intracellular half-life (17 h) of the active bisphosphorylated metabolite enables once-daily dosing. The most prominent adverse effect of adefovir dipivoxil is nephrotoxicity (which has prevented the drug from being marketed for HIV infections where the drug required administration at higher doses).

Chemical properties

White Solid

Originator

Institute of Organic Chemistry and Biochemistry of the Academy of Sciences in the Czech Republic and the REGA Stichting Research (Czech Republic, Belgium)

The Uses of Adefovir dipivoxil

Adefovir Dipivoxil(Preveon, Hepsera) works by blocking reverse transcriptase, an enzyme that is crucial for the hepatitis B virus (HBV) to reproduce in the body. It is approved for the treatment of chronic hepatitis B in adults with evidence of active vir

The Uses of Adefovir dipivoxil

A nucleotide analog, useful as an oral reverse transcriptase inhibitor (ntRTI).

What are the applications of Application

Adefovir dipivoxil is an antiviral acyclic nucleoside phosphonate (ANP) analog

Background

Adefovir dipivoxil, previously called bis-POM PMEA, with trade names Preveon and Hepsera, is an orally-administered acyclic nucleotide analog reverse transcriptase inhibitor (ntRTI) used for treatment of hepatitis B. It is ineffective against HIV-1. Adefovir dipivoxil is the diester prodrug of adefovir.

Indications

Indicated for the treatment of chronic hepatitis B in adult patients with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease; this is based on histological, virological, biochemical, and serological responses in adult patients with HBeAg+ and HBeAg- chronic hepatitis B with compensated liver function, and in adult patients with clinical evidence of lamivudine-resistant hepatitis B virus with either compensated or decompensated liver function.

Definition

ChEBI: Adefovir pivoxil is an organic phosphonate that is the dipivoxil ester of adefovir. A prodrug for adefovir, an HIV-1 reverse transcriptase inhibitor, adefovir pivoxil is used to treat chronic hepatitis B viral infection. It has a role as a prodrug, an antiviral drug, a DNA synthesis inhibitor, a HIV-1 reverse transcriptase inhibitor and a nephrotoxic agent. It is an organic phosphonate, a member of 6-aminopurines, an ether and a carbonate ester. It is functionally related to an adefovir.

brand name

Hepsera (Gilead Sciences).

General Description

Adefovir is an orally active prodrug that is indicated for thetreatment of the chronic form of hepatitis B. The dipivoxil moieties are hydrolyzed by ubiquitous esterases to yieldadefovir, which is phosphorylated by adenylate kinase toyield adefovir diphosphate. This compound is inhibitory atHBV DNA polymerase. In addition, adefovir undergoes incorporationinto viral DNA and causes chain termination.Adefovir is poorly absorbed by the oral route, but the dipivoxilester groups cause the bioavailability to increase toapproximately 60%.

Mechanism of action

Adefovir dipivoxil is an orally active prodrug indicated for the treatment of chronic hepatitis B. The drug is hydrolyzed by extracellular esterases to produce adefovir, which in turn is phosphorylated by adenylate kinase to adefovir diphosphate, which inhibits HBV DNA polymerase. Incorporation of adefovir into viral DNA also leads to DNA chain termination. As shown in Figure 43.9, adefovir dipivoxyl is activated in two steps involving an esterase that exposes a free phosphate group (adefovir), followed by addition of a second phosphate by adenylate kinase to form adefovir diphosphate, the active form of the drug.

Pharmacokinetics

Adefovir dipivoxil a diester prodrug of adefovir. Adefovir is an acyclic nucleotide analog with activity against human hepatitis B virus (HBV). The concentration of adefovir that inhibited 50% of viral DNA synthesis (IC50) in vitro ranged from 0.2 to 2.5 μM in HBV transfected human hepatoma cell lines. The combination of adefovir with lamivudine showed additive anti-HBV activity.

Clinical Use

Adefovir dipivoxil joins interferon and lamivudine in the treatment of chronic HBV. It can be used singly or in combination with lamivudine. Early clinical studies indicate benefit of the use of adefovir dipivoxil to treat lamivudine-resistant HBV with a low level of resistant virus developing to monotherapy with adefovir dipivoxil.

Synthesis

Steroidal dutasteride (5) was synthesized from 3-oxo-4- androstene-17|?-carboxylic acid (55). Oxidation of 55 with potassium permanganate, sodium periodate and sodium carbonate in refluxing t-butyl alcohol and water gave secosteroid 56 which was cyclized with ammonium acetate in acetic acid to give 4-aza-steroid 57 in good yield. Stereoselective hydrogenation of 57 with H2 over PtO2 in hot acetic acid and in the presence of ammonium acetate yielded saturated azasteroid 58, which was dehydrogenated with DDQ in the presence of bis(trimethylsilyl)trifluoroacetamide (BSTFA) 59 in refluxing dioxane to give 60. Treatment of 60 with thionyl chloride gave the corresponding acyl chloride intermediate, which was then condensed with 2,5- bis(trifluoromethyl)aniline (61) by means of DMAP in heated toluene to give dutasteride (5) in 57% yield from intermediate 60.
Synthesis_142340-99-6

Drug interactions

Potentially hazardous interactions with other drugs
Use with caution in combination with other nephrotoxins.
Antivirals: avoid concomitant administration with tenofovir
Interferons: use with caution with peginterferon alfa.

Metabolism

Following oral administration, adefovir dipivoxil is rapidly converted to adefovir. 45% of the dose is recovered as adefovir in the urine over 24 hours at steady state following 10 mg oral doses. Adefovir is not a substrate of the cytochrome P450 enzymes.

Metabolism

Adefovir is poorly absorbed orally, but the bioavailability of adefovir dipivoxil reaches approximately 59%. The drug is absorbed to an equal extent with or without the presence of food. Adefovir is excreted renally unchanged.

Properties of Adefovir dipivoxil

Melting point: 98-102°C
Boiling point: 641.0±65.0 °C(Predicted)
Density  1.35±0.1 g/cm3(Predicted)
storage temp.  Keep in dark place,Inert atmosphere,Store in freezer, under -20°C
solubility  ethanol: soluble50mg/mL
form  solid
pka 4.16±0.10(Predicted)
color  White to Off-White
Merck  14,151
CAS DataBase Reference 142340-99-6(CAS DataBase Reference)

Safety information for Adefovir dipivoxil

Signal word Warning
Pictogram(s)
ghs
Exclamation Mark
Irritant
GHS07
Precautionary Statement Codes P261:Avoid breathing dust/fume/gas/mist/vapours/spray.
P264:Wash hands thoroughly after handling.
P264:Wash skin thouroughly after handling.
P280:Wear protective gloves/protective clothing/eye protection/face protection.
P301+P312:IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.

Computed Descriptors for Adefovir dipivoxil

InChIKey WOZSCQDILHKSGG-UHFFFAOYSA-N

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