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药品详细

Zidovudine(齐多夫定)

化学结构式图
中文名
齐多夫定
英文名
Zidovudine
分子式
C10H13N5O4
化学名
1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)oxolan-2-yl]-5-methyl-1,2,3,4-tetrahydropyrimidine-2,4-dione
分子量
Average: 267.2413
Monoisotopic: 267.096753929
CAS号
30516-87-1
ATC分类
J05A Direct acting antivirals
药物类型
small molecule
阶段
approved
商品名
Apo-Zidovudine;Azidothymidine;Aztec;Compound S;Novo-Azt;Retrovir;Zidovudine EP III;
同义名
基本介绍

A dideoxynucleoside compound in which the 3'-hydroxy group on the sugar moiety has been replaced by an azido group. This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains. The compound is a potent inhibitor of HIV replication, acting as a chain-terminator of viral DNA during reverse transcription. It improves immunologic function, partially reverses the HIV-induced neurological dysfunction, and improves certain other clinical abnormalities associated with AIDS. Its principal toxic effect is dose-dependent suppression of bone marrow, resulting in anemia and leukopenia. [PubChem]

生产厂家
  • Aurobindo pharma ltd
  • Aurobindo pharma ltd inc
  • Cipla ltd
  • Hetero drugs ltd unit iii
  • Matrix laboratories ltd
  • Pharmaforce inc
  • Ranbaxy laboratories ltd
  • Roxane laboratories inc
  • Viiv healthcare co
封装厂家
参考
Synthesis Reference Not Available
General Reference
  1. De Clercq E: HIV resistance to reverse transcriptase inhibitors. Biochem Pharmacol. 1994 Jan 20;47(2):155-69. Pubmed
  2. Yarchoan R, Mitsuya H, Broder S: AIDS therapies. Sci Am. 1988 Oct;259(4):110-9. Pubmed
  3. Connor EM, Sperling RS, Gelber R, Kiselev P, Scott G, O’Sullivan MJ, VanDyke R, Bey M, Shearer W, Jacobson RL, et al.: Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 1994 Nov 3;331(18):1173-80. Pubmed
  4. Mitsuya H, Yarchoan R, Broder S: Molecular targets for AIDS therapy. Science. 1990 Sep 28;249(4976):1533-44. Pubmed
  5. Mitsuya H, Weinhold KJ, Furman PA, St Clair MH, Lehrman SN, Gallo RC, Bolognesi D, Barry DW, Broder S: 3’-Azido-3’-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. Proc Natl Acad Sci U S A. 1985 Oct;82(20):7096-100. Pubmed
  6. Court MH, Krishnaswamy S, Hao Q, Duan SX, Patten CJ, Von Moltke LL, Greenblatt DJ: Evaluation of 3’-azido-3’-deoxythymidine, morphine, and codeine as probe substrates for UDP-glucuronosyltransferase 2B7 (UGT2B7) in human liver microsomes: specificity and influence of the UGT2B7*2 polymorphism. Drug Metab Dispos. 2003 Sep;31(9):1125-33. Pubmed
剂型
规格
化合物类型
Type small molecule
Classes
  • Pyrimidines and Derivatives
Substructures
  • Hydroxy Compounds
  • Ethers
  • Azides
  • Alcohols and Polyols
  • Pyrimidines and Derivatives
  • Heterocyclic compounds
  • Aromatic compounds
  • Furans
  • Cyanamides
适应症
ANTIVIRALS 抗病毒;
药理
Indication Used in combination with other antiretroviral agents for the treatment of human immunovirus (HIV) infections.
Pharmacodynamics Zidovudine is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Zidovudine is phosphorylated to active metabolites that compete for incorporation into viral DNA. They inhibit the HIV reverse transcriptase enzyme competitively and act as a chain terminator of DNA synthesis. The lack of a 3'-OH group in the incorporated nucleoside analogue prevents the formation of the 5' to 3' phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is terminated.
Mechanism of action Zidovudine, a structural analog of thymidine, is a prodrug that must be phosphorylated to its active 5′-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). It inhibits the activity of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue. It competes with the natural substrate dGTP and incorporates itself into viral DNA. It is also a weak inhibitor of cellular DNA polymerase α and γ.
Absorption Rapid and nearly complete absorption from the gastrointestinal tract following oral administration; however, because of first-pass metabolism, systemic bioavailability of zidovudine capsules and solution is approximately 65% (range, 52 to 75%). Bioavailability in neonates up to 14 days of age is approximately 89%, and it decreases to approximately 61% and 65% in neonates over 14 days of age and children 3 months to 12 years, respectively. Administration with a high-fat meal may decrease the rate and extent of absorption.
Volume of distribution

Apparent volume of distribution, HIV-infected patients, IV administration = 1.6 ± 0.6 L/kg
Protein binding 30-38%
Metabolism
Hepatic. Metabolized by glucuronide conjugation to major, inactive metabolite, 3′-azido-3′-deoxy-5′- O-beta-D-glucopyranuronosylthymidine (GZDV). UGT2B7 is the primary UGT isoform that is responsible for glucuronidation. Compared to zidovudine, GZDV's area under the curve is approximately 3-fold greater. The cytochrome P450 isozymes are responsible for the reduction of the azido moiety to form 3'-amino-3'- deoxythymidine (AMT).

Important The metabolism module of DrugBank is currently in beta. Questions or suggestions? Please contact us.

Substrate Enzymes Product
Zidovudine
    		3'-azido-3'-deoxy-5'- O-beta-D-glucopyranuronosylthymidine Details
    Zidovudine
      		3’-amino-3’-deoxythimidine Details
      Zidovudine
        		3’-amino-3’-deoxythimidine glucuronide Details
        Zidovudine
          		5’glucuronyl zidovudine Details
          Route of elimination As in adult patients, the major route of elimination was by metabolism to GZDV. After intravenous dosing, about 29% of the dose was excreted in the urine unchanged and about 45% of the dose was excreted as GZDV.
          Half life Elimination half life, HIV-infected patients, IV administration = 1.1 hours (range of 0.5 - 2.9 hours)
          Clearance
          • 0.65 +/- 0.29 L/hr/kg [HIV-infected, Birth to 14 Days of Age]
          • 1.14 +/- 0.24 L/hr/kg [HIV-infected, 14 Days to 3 Months of Age]
          • 1.85 +/- 0.47 L/hr/kg [HIV-infected, 3 Months to 12 Years of Age].
            The transporters, ABCB1, ABCC4, ABCC5, and ABCG2 are involved with the clearance of zidovudine.
          Toxicity Symptoms of overdose include fatigue, headache, nausea, and vomiting. LD50 is 3084 mg/kg (orally in mice).
          Affected organisms
          • Human Immunodeficiency Virus
          Pathways Not Available
          理化性质
          Properties
          State solid
          Experimental Properties
          Property Value Source
          melting point 113-115 °C PhysProp
          water solubility 2.01E+004 mg/L (at 25 °C) PHYSICIANS DESK REFERENCE (2003)
          logP 0.05 HANSCH,C ET AL. (1995)
          Caco2 permeability -5.16 ADME Research, USCD
          Predicted Properties
          Property Value Source
          water solubility 1.63e+01 g/l ALOGPS
          logP -0.1 ALOGPS
          logP -0.3 ChemAxon
          logS -1.2 ALOGPS
          pKa (strongest acidic) 9.96 ChemAxon
          pKa (strongest basic) -3 ChemAxon
          physiological charge 0 ChemAxon
          hydrogen acceptor count 6 ChemAxon
          hydrogen donor count 2 ChemAxon
          polar surface area 108.3 ChemAxon
          rotatable bond count 3 ChemAxon
          refractivity 61.7 ChemAxon
          polarizability 24.93 ChemAxon
          药物相互作用
          Drug Interaction
          Atovaquone Atovaquone increases the effect and toxicity of zidovudine
          Clarithromycin Clarithromycin may decrease the serum concentration of zidovudine. Increased myelosuppression in mice has been observed. Consider staggering doses during concomitant therapy and closely monitor response to zidovudine therapy.
          Doxorubicin Additive myelosuppression may occur. Doxorubicin may decrease the efficacy of zidovudine. Concomitant therapy should be avoided.
          Ganciclovir Increased risk of hematologic toxicity. Concomitant therapy should be avoided.
          Interferon beta-1b The interferon increases the effect and toxicity of zidovudine
          Methadone Methadone increases the effect and toxicity of zidovudine
          Probenecid Rash, malaise, myalgia
          Ribavirin Increased risk or severity of anemia. Consider alternate therapy or monitor more closely for anemia.
          Rifabutin The rifamycin decreases levels of zidovudine
          Rifampin Rifampin may decrease the serum concentration of zidovudine by increasing its metabolism. Monitor for changes in the serum concentration and therapeutic and adverse effects of zidovudine if rifampin is initiated, discontinued or dose changed.
          Rifapentine Rifapentin may decrease the serum concentration of zidovudine by increasing its metabolism. Monitor for changes in the serum concentration and therapeutic and adverse effects of zidovudine if rifapentin is initiated, discontinued or dose changed.
          Stavudine Zidovudine may decrease the efficacy of stavudine. Concomitant therapy should be avoided.
          Tipranavir Tipranavir decreases the concentration of Zidovudine.
          Valganciclovir The adverse/toxic effects of Zidovudine, a reverse transcriptase inhibitor (nucleoside), may be enhanced by Valganciclovir. There is a significant risk of hematologic toxicity. Concomitant therapy should be avoided.
          食物相互作用
          Not Available

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