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药品详细

Adefovir Dipivoxil(阿德福韦酯)

化学结构式图
中文名
阿德福韦酯
英文名
Adefovir Dipivoxil
分子式
C20H32N5O8P
化学名
[({[2-(6-amino-9H-purin-9-yl)ethoxy]methyl}({[(2,2-dimethylpropanoyl)oxy]methoxy})phosphoryl)oxy]methyl 2,2-dimethylpropanoate
分子量
Average: 501.4705
Monoisotopic: 501.198849537
CAS号
142340-99-6
ATC分类
J05A Direct acting antivirals
药物类型
small molecule
阶段
approved
商品名
Hepsera;Preveon;
同义名
Adefovir;adefovir dipivoxil;Adefovir pivoxil;Adefovirdipivoxl;ADV;bis-POM PMEA;GS-840;PMEA;
基本介绍

Adefovir dipivoxil, previously called bis-POM PMEA, with trade names Preveon and Hepsera, is an orally-administered nucleotide analog reverse transcriptase inhibitor (ntRTI) used for treatment of hepatitis B. It is a failed treatment for HIV. [Wikipedia]

生产厂家
  • Gilead sciences inc
封装厂家
参考
Synthesis Reference Not Available
General Reference Not Available
剂型
规格
化合物类型
Type small molecule
Classes
  • Purines and Purine Derivatives
Substructures
  • Carbonyl Compounds
  • Carboxylic Acids and Derivatives
  • Acetates
  • Phosphonic Acids and Derivatives
  • Aliphatic and Aryl Amines
  • Ethers
  • Pyrimidines and Derivatives
  • Imidazoles
  • Heterocyclic compounds
  • Aromatic compounds
  • Purines and Purine Derivatives
  • Phosphinic Acids and Derivatives
  • Cyanamides
适应症
ANTIVIRALS 抗病毒;
药理
Indication For the treatment of chronic hepatitis B in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.
Pharmacodynamics 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.
Mechanism of action Adefovir dipivoxil is a prodrug of adefovir. Adefovir is an acyclic nucleotide analog of adenosine monophosphate which is phosphorylated to the active metabolite adefovir diphosphate by cellular kinases. Adefovir diphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate deoxyadenosine triphosphate and by causing DNA chain termination after its incorporation into viral DNA. The inhibition constant (Ki) for adefovir diphosphate for HBV DNA polymerase was 0.1 μM. Adefovir diphosphate is a weak inhibitor of human DNA polymerases α and γ with Ki values of 1.18 μM and 0.97μM, respectively.
Absorption Approximate oral bioavailability is 59%.
Volume of distribution
  • 392 ± 75 mL/kg [intravenous administration of 1.0 mg/kg/day]
  • 352 ± 9 mL/kg [intravenous administration of 3.0 mg/kg/day]
Protein binding ≤4% over the adefovir concentration range of 0.1 to 25 μg/mL
Metabolism
Following oral administration, adefovir dipivoxil is rapidly converted to adefovir. Forty-five percent 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.
Route of elimination Adefovir is renally excreted by a combination of glomerular filtration and active tubular secretion.
Half life Terminal elimination half-life of 7.48 ± 1.65 hours
Clearance
  • 469 +/- 99.0 mL/min [Patients with Unimpaired renal Function receiving a 10 mg single dose]
  • 356 +/- 85.6 mL/min [Patients with mild renal impairement receiving a 10 mg single dose]
  • 237 +/- 118 mL/min [Patients with moderate renal impairement receiving a 10 mg single dose]
  • 91.7+/- 51.3 mL/min [Patients with severe renal impairement receiving a 10 mg single dose]
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.
Affected organisms
  • Hepatitis B virus
Pathways
Pathway Name SMPDB ID
Smp00418 Adefovir Dipivoxil Pathway SMP00418
理化性质
Properties
State solid
Experimental Properties
Property Value Source
water solubility 19 mg/mL at pH 2.0 and 0.4 mg/mL at pH 7.2. Not Available
logP 0.8 Not Available
Predicted Properties
Property Value Source
water solubility 6.33e-01 g/l ALOGPS
logP 1.49 ALOGPS
logP 3.06 ChemAxon
logS -2.9 ALOGPS
pKa (strongest acidic) 18.59 ChemAxon
pKa (strongest basic) 5.13 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 8 ChemAxon
hydrogen donor count 1 ChemAxon
polar surface area 166.98 ChemAxon
rotatable bond count 15 ChemAxon
refractivity 119.99 ChemAxon
polarizability 49 ChemAxon
药物相互作用
Drug Interaction
Valganciclovir The adverse/toxic effects of reverse transcriptase inhibitors (nucleoside), such as Adefovir Dipivoxil, may be enhanced by Valganciclovir. There is a risk of hematologic toxicity. Diligent monitoring during concomitant therapy is recommended.
食物相互作用
  • Take without regard to meals.

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