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Tenofovir disoproxil

Tenofovir disoproxil, sold under the trade name Viread among others, is a medication used to treat chronic hepatitis B and to prevent and treat HIV/AIDS.[1] It is generally recommended for use with other antiretrovirals.[1] It may be used for prevention of HIV/AIDS among those at high risk before exposure, and after a needlestick injury or other potential exposure.[1] It is sold both by itself and together in combinations such as emtricitabine/tenofovir, efavirenz/emtricitabine/tenofovir,[1] and elvitegravir/cobicistat/emtricitabine/tenofovir.[2] It does not cure HIV/AIDS or hepatitis B.[1][3] It is available by mouth as a tablet or powder.[1]

Tenofovir disoproxil
Clinical data
Pronunciation/ˌtəˈnfəvɪər ˌdɪsəˈprɑːksəl/
Trade namesViread, others
Other namesBis(POC)PMPA
AHFS/Drugs.comMonograph
MedlinePlusa602018
License data
Pregnancy
category
  • AU: B3
Routes of
administration
By mouth (tablets)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability25%
MetabolismEster hydrolysis
MetabolitesTenofovir
Identifiers
  • Bis{[(isopropoxycarbonyl)oxy]methyl} ({[(2R)-1-(6-amino-9H-purin-9-yl)-2-propanyl]oxy}methyl)phosphonate
CAS Number
  • 201341-05-1
PubChem CID
  • 5481350
DrugBank
  • DB00300
ChemSpider
  • 4587262
UNII
  • F4YU4LON7I
KEGG
  • C13480
ChEBI
  • CHEBI:63717
ChEMBL
  • ChEMBL1538
NIAID ChemDB
  • 080741
CompTox Dashboard (EPA)
  • DTXSID9040132
ECHA InfoCard100.129.993
Chemical and physical data
FormulaC19H30N5O10P
Molar mass519.448 g·mol−1
3D model (JSmol)
  • Interactive image
  • C[C@H](Cn1cnc2c1ncnc2N)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C
  • InChI=1S/C19H30N5O10P/c1-12(2)33-18(25)28-9-31-35(27,32-10-29-19(26)34-13(3)4)11-30-14(5)6-24-8-23-15-16(20)21-7-22-17(15)24/h7-8,12-14H,6,9-11H2,1-5H3,(H2,20,21,22)/t14-/m1/s1
  • Key:JFVZFKDSXNQEJW-CQSZACIVSA-N
Tenofovir
Clinical data
Other names9-(2-Phosphonyl-methoxypropyly)adenine (PMPA)
MedlinePlusa602018
ATC code
  • None
Pharmacokinetic data
Protein binding< 1%
MetabolismPhosphorylation
MetabolitesTenofovir diphosphate (active metabolite)
Elimination half-life17 hours
ExcretionKidney
Identifiers
  • ({[(2R)-1-(6-amino-9H-purin-9-yl)propan-2-yl]oxy}methyl)phosphonic acid
CAS Number
  • 147127-20-6 Y
PubChem CID
  • 464205
DrugBank
  • DB14126 Y
ChemSpider
  • 408154 Y
UNII
  • 99YXE507IL
KEGG
  • D06074 Y
ChEBI
  • CHEBI:63625
ChEMBL
  • ChEMBL483 Y
CompTox Dashboard (EPA)
  • DTXSID9040132
ECHA InfoCard100.129.993
Chemical and physical data
FormulaC9H14N5O4P
Molar mass287.216 g·mol−1
3D model (JSmol)
  • Interactive image
  • O=P(O)(O)CO[C@H](C)Cn1c2ncnc(c2nc1)N
  • InChI=1S/C9H14N5O4P/c1-6(18-5-19(15,16)17)2-14-4-13-7-8(10)11-3-12-9(7)14/h3-4,6H,2,5H2,1H3,(H2,10,11,12)(H2,15,16,17)/t6-/m1/s1 Y
  • Key:SGOIRFVFHAKUTI-ZCFIWIBFSA-N Y
  (verify)

Common side effects include nausea, rash, diarrhea, headache, pain, depression, and weakness.[1] Severe side effects include high blood lactate and an enlarged liver.[1] There are no absolute contraindications.[1] It is often recommended during pregnancy and appears to be safe.[1] It is a nucleotide reverse transcriptase inhibitor and works by decreasing the ability of the viruses to replicate.[1]

Tenofovir was patented in 1996 and approved for use in the United States in 2001.[4] It is on the World Health Organization's List of Essential Medicines.[5] It is available in the United States as a generic medication as of 2017.[6]

Medical uses

Tenofovir disoproxil is used for HIV-1 infection and chronic hepatitis B treatment. For HIV-1 infection, tenofovir is indicated in combination with other antiretroviral agents for people 2 years of age and older. For chronic hepatitis B patients, tenofovir is indicated for patients 12 years of age and older.[7]

HIV risk reduction

Tenofovir can be used for HIV prevention in people who are at high risk for infection through sexual transmission or injecting drug use. A Cochrane review examined the use of tenofovir for prevention of HIV before exposure and found that both tenofovir alone and the tenofovir/emtricitabine combination decreased the risk of contracting HIV for high risk patients.[8] The U.S. Centers for Disease Control and Prevention (CDC) also conducted a study in partnership with the Thailand Ministry of Public Health to ascertain the effectiveness of providing people who inject drugs illicitly with daily doses of tenofovir as a prevention measure. The results revealed a 48.9% reduced incidence of the virus among the group of subjects who received the drug in comparison to the control group who received a placebo.[9]

Adverse effects

Tenofovir disoproxil is generally well tolerated with low discontinuation rates among the HIV and chronic hepatitis B population.[10] There are no contraindications for use of this drug.[7] The most commonly reported side effects due to use of tenofovir disoproxil were dizziness, nausea, and diarrhea.[10] Other adverse effects include depression, sleep disturbances, headache, itching, rash, and fever. The US boxed warning cautions potential onset of lactic acidosis or liver damage due to use of tenofovir disoproxil.[11]

Long term use of tenofovir disoproxil is associated with nephrotoxicity and bone loss. Presentation of nephrotoxicity can appear as Fanconi syndrome, acute kidney injury, or decline of glomerular filtration rate (GFR).[12] Discontinuation of tenofovir disoproxil can potentially lead to reversal of renal impairment. Nephrotoxicity may be due to proximal tubules accumulation of Tenofovir disoproxil leading to elevated serum concentrations.[10]

Interactions

Tenofovir interacts with didanosine and HIV-1 protease inhibitors. Tenofovir increases didanosine concentrations and can result in adverse effects such as pancreatitis and neuropathy. Tenofovir also interacts with HIV-1 protease inhibitors such as atazanavir, by decreasing atazanavir concentrations while increasing tenofovir concentrations.[7] In addition, since tenofovir is excreted by the kidney, medications that impair renal function can also cause problems.[13]

Pharmacology

Mechanism of action

Tenofovir disoproxil is a nucleotide analog reverse-transcriptase inhibitor (NtRTI).[14] It selectively inhibits viral reverse transcriptase, a crucial enzyme in retroviruses such as human immunodeficiency virus (HIV), while showing limited inhibition of human enzymes, such as DNA polymerases α, β, and mitochondrial DNA polymerase γ.[7][14] In vivo tenofovir disoproxil fumarate is converted to tenofovir, an acyclic analog of deoxyadenosine 5'-monophosphate (dAMP). Tenofovir lacks a hydroxyl group in the position corresponding to the 3' carbon of the dAMP, preventing the formation of the 5′ to 3′ phosphodiester linkage essential for DNA chain elongation.[14] Once incorporated into a growing DNA strand, tenofovir causes premature termination of DNA transcription, preventing viral replication.[14]

Pharmacokinetics

Tenofovir disoproxil is a prodrug that is quickly absorbed from the gut and cleaved to release tenofovir.[7] Inside cells, tenofovir is phosphorylated to tenofovir diphosphate (which is analogous to a triphosphate, as tenofovir itself already has one phosphonate residue), the active compound that inhibits reverse transcriptase via chain termination.[13][14]

In fasting persons, bioavailability is 25%, and highest blood plasma concentrations are reached after one hour.[14] When taken with fatty food, highest plasma concentrations are reached after two hours, and the area under the curve is increased by 40%.[14] It is an inhibitor of cytochrome P450 1A2.[15]

Tenofovir is mainly excreted via the kidneys, both by glomerular filtration and by tubular secretion using the transport proteins OAT1, OAT3 and ABCC4.[13]

Detection in body fluids

Tenofovir may be measured in plasma by liquid chromatography. Such testing is useful for monitoring therapy and to prevent drug accumulation and toxicity in people with kidney or liver problems.[16][17][18]

Chemistry

Tenofovir is a derivative of adenine and this was the chemical starting point for its first published synthesis[19] which was included in patents to the compound.[20] During drug development, attention switched to the phosphonate ester derivative, tenofovir disoproxil, which was the subject of extensive process chemistry to provide a viable manufacturing route.

 

Adenine is first reacted with a chiral version of propylene carbonate with R absolute configuration, using sodium hydroxide as base. Under these conditions, the reaction is regioselective, with alkylation occurring exclusively in the imidazole ring and at the less-hindered carbon of the dioxolane. In the second step, the hydroxyl group is reacted with a phosphonic acid derivative, using tert-butyllithium as base to ensure selective O-alkylation, with the formation of an ether bond. Tenofovir is formed when the diethyl phosphonate group is converted to its acid using trimethylsilyl chloride in the presence of sodium bromide, a further refinement of the original manufacturing route.[21][22][23] The synthesis of the alternative ester in tenofovir disoproxil is completed by alkylation with the appropriate chloromethyl ether derivative and this may be purified as its fumarate salt.[21]

History

Tenofovir was initially synthesized by Antonín Holý at the Institute of Organic Chemistry and Biochemistry of the Czechoslovak Academy of Sciences in Prague. The patent filed in 1986 makes no mention of the potential use of the compound for the treatment of HIV infection but claims activity against herpes simplex virus.[20]

In 1985, De Clercq and Holý described the activity of PMPA against HIV in cell culture.[24] Shortly thereafter, a collaboration with the biotechnology company Gilead Sciences led to the investigation of PMPA's potential as a treatment for HIV infected patients. In 1997 researchers from Gilead and the University of California, San Francisco demonstrated that tenofovir exhibits anti-HIV effects in humans when dosed by subcutaneous injection.[25]

The initial form of tenofovir used in these studies had limited potential for widespread use because it poorly penetrated cells and was not absorbed when given by mouth. Gilead developed a pro-drug version of tenofovir, tenofovir disoproxil. This version of tenofovir is often referred to simply as "tenofovir". In this version of the drug, the two negative charges of the tenofovir phosphonic acid group are masked, thus enhancing oral absorption.

Tenofovir disoproxil was approved in the U.S. in 2001, for the treatment of HIV, and in 2008, for the treatment of chronic hepatitis B.[26][27]

Drug forms

Tenofovir disoproxil can be taken by mouth and is sold under the brand name Viread, among others.[28] Tenofovir disoproxil is a pro-drug form of tenofovir phosphonate, which is liberated intracellularly and converted to tenofovir disphophate.[29] It is marketed by Gilead Sciences (as the fumarate, abbreviated TDF).[30]

Tenofovir disoproxil is also available in pills which combine a number of antiviral drugs into a single dose. Well-known combinations include Atripla (tenofovir disoproxil/emtricitabine/efavirenz), Complera (tenofovir disoproxil/emtricitabine/rilpivirine), Stribild (tenofovir disoproxil/emtricitabine/elvitegravir/cobicistat), and Truvada (tenofovir disoproxil/emtricitabine).[28]

Gilead has created a second pro-drug form of the active drug, tenofovir diphosphate, called tenofovir alafenamide. It differs from tenofovir disoproxil due to its activation in the lymphoid cells. This allows the active metabolites to accumulate in those cells, leading to lower systemic exposure and potential toxicities.[10]

References

  1. ^ a b c d e f g h i j k "Tenofovir Disoproxil Fumarate". The American Society of Health-System Pharmacists. from the original on 30 November 2016. Retrieved 29 November 2016.
  2. ^ "Stribild". PubChem. U.S. National Library of Medicine. Retrieved 6 February 2022.
  3. ^ Martin P, Lau DT, Nguyen MH, Janssen HL, Dieterich DT, Peters MG, Jacobson IM (November 2015). "A Treatment Algorithm for the Management of Chronic Hepatitis B Virus Infection in the United States: 2015 Update". Clinical Gastroenterology and Hepatology. 13 (12): 2071–87.e16. doi:10.1016/j.cgh.2015.07.007. PMID 26188135.
  4. ^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 505. ISBN 9783527607495. from the original on 2017-09-08.
  5. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  6. ^ . www.tevapharm.com. Archived from the original on 2018-11-06. Retrieved 2018-11-06.
  7. ^ a b c d e (PDF). Gilead Sciences, Inc. November 2012. Archived from the original (PDF) on 7 February 2013.
  8. ^ Okwundu CI, Uthman OA, Okoromah CA (July 2012). "Antiretroviral pre-exposure prophylaxis (PrEP) for preventing HIV in high-risk individuals". The Cochrane Database of Systematic Reviews. 7 (7): CD007189. doi:10.1002/14651858.CD007189.pub3. PMID 22786505.
  9. ^ Bourke E (14 June 2013). "Preventive drug could reduce HIV transmission among injecting drug users". The Conversation Australia. The Conversation Media Group. from the original on 1 November 2013. Retrieved 17 June 2013.
  10. ^ a b c d Ustianowski A, Arends JE (June 2015). "Tenofovir: What We Have Learnt After 7.5 Million Person-Years of Use". Infectious Diseases and Therapy. 4 (2): 145–57. doi:10.1007/s40121-015-0070-1. PMC 4471058. PMID 26032649.
  11. ^ "Tenofovir: MedlinePlus Drug Information". MedlineP. U.S. National Library of Medicine. from the original on 2016-11-10. Retrieved 2016-11-09.
  12. ^ Morlat P, Vivot A, Vandenhende MA, Dauchy FA, Asselineau J, Déti E, Gerard Y, Lazaro E, Duffau P, Neau D, Bonnet F, Chêne G (2013-06-12). "Role of traditional risk factors and antiretroviral drugs in the incidence of chronic kidney disease, ANRS CO3 Aquitaine cohort, France, 2004-2012". PLOS ONE. 8 (6): e66223. Bibcode:2013PLoSO...866223M. doi:10.1371/journal.pone.0066223. PMC 3680439. PMID 23776637.
  13. ^ a b c Haberfeld, H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
  14. ^ a b c d e f g . DrugBank. Archived from the original on 8 September 2015.
  15. ^ "Tenofovir disoproxil". Pubchem. U.S. National Library of Medicine. Retrieved 2018-04-17.
  16. ^ Delahunty T, Bushman L, Robbins B, Fletcher CV (July 2009). "The simultaneous assay of tenofovir and emtricitabine in plasma using LC/MS/MS and isotopically labeled internal standards". Journal of Chromatography B. 877 (20–21): 1907–14. doi:10.1016/j.jchromb.2009.05.029. PMC 2714254. PMID 19493710.
  17. ^ Kearney BP, Yale K, Shah J, Zhong L, Flaherty JF (2006). "Pharmacokinetics and dosing recommendations of tenofovir disoproxil fumarate in hepatic or renal impairment". Clinical Pharmacokinetics. 45 (11): 1115–24. doi:10.2165/00003088-200645110-00005. PMID 17048975. S2CID 6322957.
  18. ^ Baselt R (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, California: Biomedical Publications. pp. 1490–1492.
  19. ^ Holý A, Rosenberg I (1982). "Preparation of 5'-O-phosphonylmethyl analogues of nucleoside-5'-phosphates, 5'-diphosphates and 5'-triphosphates". Collection of Czechoslovak Chemical Communications. 47 (12): 3447–3463. doi:10.1135/cccc19823447.
  20. ^ a b US patent 4808716, Holy A, Rosenberg I, "9-(phosponylmethoxyalkyl) adenines, the method of preparation and utilization thereof", published 1989-02-28, assigned to Czech Academy of Sciences 
  21. ^ a b Brown Ripin DH, Teager DS, Fortunak J, Basha SM, Bivins N, Boddy CN, et al. (2010). "Process Improvements for the Manufacture of Tenofovir Disoproxil Fumarate at Commercial Scale". Organic Process Research & Development. 14 (5): 1194–1201. doi:10.1021/op1001337.
  22. ^ Houghton SR, Melton J, Fortunak J, Brown Ripin DH, Boddy CN (2010). "Rapid, mild method for phosphonate diester hydrolysis: Development of a one-pot synthesis of tenofovir disoproxil fumarate from tenofovir diethyl ester". Tetrahedron. 66 (41): 8137–8144. doi:10.1016/j.tet.2010.08.037.
  23. ^ Vardanyan R, Hruby V (2016). "34: Antiviral Drugs". Synthesis of Best-Seller Drugs. pp. 714–716. doi:10.1016/B978-0-12-411492-0.00034-1. ISBN 9780124114920. S2CID 75449475.
  24. ^ US 4724233, De Clercq E, Holy A, Rosenberg I, "Therapeutical application of phosphonylmethoxyalkyl adenines" 
  25. ^ Deeks SG, Barditch-Crovo P, Lietman PS, Hwang F, Cundy KC, Rooney JF, Hellmann NS, Safrin S, Kahn JO (September 1998). "Safety, pharmacokinetics, and antiretroviral activity of intravenous 9-[2-(R)-(Phosphonomethoxy)propyl]adenine, a novel anti-human immunodeficiency virus (HIV) therapy, in HIV-infected adults". Antimicrobial Agents and Chemotherapy. 42 (9): 2380–4. doi:10.1128/aac.42.9.2380. PMC 105837. PMID 9736567.
  26. ^ Shwiff K. (PDF). Food and Drug Administration. Archived from the original (PDF) on 25 February 2009.
  27. ^ Shwiff, Kathy (11 August 2008). . The Wall Street Journal. Dow Jones & Company, Inc. Archived from the original on 8 September 2017.
  28. ^ a b "Drugs@FDA: FDA Approved Drug Products". www.accessdata.fda.gov. from the original on 2016-11-10. Retrieved 2016-11-09.
  29. ^ Mouton JP, Cohen K, Maartens G (November 2016). "Key toxicity issues with the WHO-recommended first-line antiretroviral therapy regimen". Expert Review of Clinical Pharmacology. 9 (11): 1493–1503. doi:10.1080/17512433.2016.1221760. PMID 27498720. S2CID 205930751.
  30. ^ Emau P, Jiang Y, Agy MB, Tian B, Bekele G, Tsai CC (November 2006). "Post-exposure prophylaxis for SIV revisited: animal model for HIV prevention". AIDS Research and Therapy. 3: 29. doi:10.1186/1742-6405-3-29. PMC 1687192. PMID 17132170.

External links

  • "Tenofovir disoproxil". Drug Information Portal. U.S. National Library of Medicine.
  • "Tenofovir disoproxil fumarate". Drug Information Portal. U.S. National Library of Medicine.

tenofovir, disoproxil, tenofovir, redirects, here, prodrug, tenofovir, medication, treatment, chronic, hepatitis, virus, tenofovir, alafenamide, sold, under, trade, name, viread, among, others, medication, used, treat, chronic, hepatitis, prevent, treat, aids,. Tenofovir redirects here For the prodrug of tenofovir and medication for the treatment of chronic hepatitis B virus see Tenofovir alafenamide Tenofovir disoproxil sold under the trade name Viread among others is a medication used to treat chronic hepatitis B and to prevent and treat HIV AIDS 1 It is generally recommended for use with other antiretrovirals 1 It may be used for prevention of HIV AIDS among those at high risk before exposure and after a needlestick injury or other potential exposure 1 It is sold both by itself and together in combinations such as emtricitabine tenofovir efavirenz emtricitabine tenofovir 1 and elvitegravir cobicistat emtricitabine tenofovir 2 It does not cure HIV AIDS or hepatitis B 1 3 It is available by mouth as a tablet or powder 1 Tenofovir disoproxilClinical dataPronunciation ˌ t e ˈ n oʊ f e v ɪer ˌ d ɪ s e ˈ p r ɑː k s el Trade namesViread othersOther namesBis POC PMPAAHFS Drugs comMonographMedlinePlusa602018License dataEU EMA by INN US DailyMed Tenofovir disoproxilPregnancycategoryAU B3Routes ofadministrationBy mouth tablets ATC codeJ05AF07 WHO Legal statusLegal statusAU S4 Prescription only CA only UK POM Prescription only US only EU Rx onlyPharmacokinetic dataBioavailability25 MetabolismEster hydrolysisMetabolitesTenofovirIdentifiersIUPAC name Bis isopropoxycarbonyl oxy methyl 2R 1 6 amino 9H purin 9 yl 2 propanyl oxy methyl phosphonateCAS Number201341 05 1PubChem CID5481350DrugBankDB00300ChemSpider4587262UNIIF4YU4LON7IKEGGC13480ChEBICHEBI 63717ChEMBLChEMBL1538NIAID ChemDB080741CompTox Dashboard EPA DTXSID9040132ECHA InfoCard100 129 993Chemical and physical dataFormulaC 19H 30N 5O 10PMolar mass519 448 g mol 13D model JSmol Interactive imageSMILES C C H Cn1cnc2c1ncnc2N OCP O OCOC O OC C C OCOC O OC C CInChI InChI 1S C19H30N5O10P c1 12 2 33 18 25 28 9 31 35 27 32 10 29 19 26 34 13 3 4 11 30 14 5 6 24 8 23 15 16 20 21 7 22 17 15 24 h7 8 12 14H 6 9 11H2 1 5H3 H2 20 21 22 t14 m1 s1Key JFVZFKDSXNQEJW CQSZACIVSA NTenofovirClinical dataOther names9 2 Phosphonyl methoxypropyly adenine PMPA MedlinePlusa602018ATC codeNonePharmacokinetic dataProtein binding lt 1 MetabolismPhosphorylationMetabolitesTenofovir diphosphate active metabolite Elimination half life17 hoursExcretionKidneyIdentifiersIUPAC name 2R 1 6 amino 9H purin 9 yl propan 2 yl oxy methyl phosphonic acidCAS Number147127 20 6 YPubChem CID464205DrugBankDB14126 YChemSpider408154 YUNII99YXE507ILKEGGD06074 YChEBICHEBI 63625ChEMBLChEMBL483 YCompTox Dashboard EPA DTXSID9040132ECHA InfoCard100 129 993Chemical and physical dataFormulaC 9H 14N 5O 4PMolar mass287 216 g mol 13D model JSmol Interactive imageSMILES O P O O CO C H C Cn1c2ncnc c2nc1 NInChI InChI 1S C9H14N5O4P c1 6 18 5 19 15 16 17 2 14 4 13 7 8 10 11 3 12 9 7 14 h3 4 6H 2 5H2 1H3 H2 10 11 12 H2 15 16 17 t6 m1 s1 YKey SGOIRFVFHAKUTI ZCFIWIBFSA N Y verify Common side effects include nausea rash diarrhea headache pain depression and weakness 1 Severe side effects include high blood lactate and an enlarged liver 1 There are no absolute contraindications 1 It is often recommended during pregnancy and appears to be safe 1 It is a nucleotide reverse transcriptase inhibitor and works by decreasing the ability of the viruses to replicate 1 Tenofovir was patented in 1996 and approved for use in the United States in 2001 4 It is on the World Health Organization s List of Essential Medicines 5 It is available in the United States as a generic medication as of 2017 6 Contents 1 Medical uses 1 1 HIV risk reduction 2 Adverse effects 3 Interactions 4 Pharmacology 4 1 Mechanism of action 4 2 Pharmacokinetics 4 3 Detection in body fluids 5 Chemistry 6 History 7 Drug forms 8 References 9 External linksMedical uses EditTenofovir disoproxil is used for HIV 1 infection and chronic hepatitis B treatment For HIV 1 infection tenofovir is indicated in combination with other antiretroviral agents for people 2 years of age and older For chronic hepatitis B patients tenofovir is indicated for patients 12 years of age and older 7 HIV risk reduction Edit Tenofovir can be used for HIV prevention in people who are at high risk for infection through sexual transmission or injecting drug use A Cochrane review examined the use of tenofovir for prevention of HIV before exposure and found that both tenofovir alone and the tenofovir emtricitabine combination decreased the risk of contracting HIV for high risk patients 8 The U S Centers for Disease Control and Prevention CDC also conducted a study in partnership with the Thailand Ministry of Public Health to ascertain the effectiveness of providing people who inject drugs illicitly with daily doses of tenofovir as a prevention measure The results revealed a 48 9 reduced incidence of the virus among the group of subjects who received the drug in comparison to the control group who received a placebo 9 Adverse effects EditTenofovir disoproxil is generally well tolerated with low discontinuation rates among the HIV and chronic hepatitis B population 10 There are no contraindications for use of this drug 7 The most commonly reported side effects due to use of tenofovir disoproxil were dizziness nausea and diarrhea 10 Other adverse effects include depression sleep disturbances headache itching rash and fever The US boxed warning cautions potential onset of lactic acidosis or liver damage due to use of tenofovir disoproxil 11 Long term use of tenofovir disoproxil is associated with nephrotoxicity and bone loss Presentation of nephrotoxicity can appear as Fanconi syndrome acute kidney injury or decline of glomerular filtration rate GFR 12 Discontinuation of tenofovir disoproxil can potentially lead to reversal of renal impairment Nephrotoxicity may be due to proximal tubules accumulation of Tenofovir disoproxil leading to elevated serum concentrations 10 Interactions EditTenofovir interacts with didanosine and HIV 1 protease inhibitors Tenofovir increases didanosine concentrations and can result in adverse effects such as pancreatitis and neuropathy Tenofovir also interacts with HIV 1 protease inhibitors such as atazanavir by decreasing atazanavir concentrations while increasing tenofovir concentrations 7 In addition since tenofovir is excreted by the kidney medications that impair renal function can also cause problems 13 Pharmacology EditMechanism of action Edit Tenofovir disoproxil is a nucleotide analog reverse transcriptase inhibitor NtRTI 14 It selectively inhibits viral reverse transcriptase a crucial enzyme in retroviruses such as human immunodeficiency virus HIV while showing limited inhibition of human enzymes such as DNA polymerases a b and mitochondrial DNA polymerase g 7 14 In vivo tenofovir disoproxil fumarate is converted to tenofovir an acyclic analog of deoxyadenosine 5 monophosphate dAMP Tenofovir lacks a hydroxyl group in the position corresponding to the 3 carbon of the dAMP preventing the formation of the 5 to 3 phosphodiester linkage essential for DNA chain elongation 14 Once incorporated into a growing DNA strand tenofovir causes premature termination of DNA transcription preventing viral replication 14 Pharmacokinetics Edit Tenofovir disoproxil is a prodrug that is quickly absorbed from the gut and cleaved to release tenofovir 7 Inside cells tenofovir is phosphorylated to tenofovir diphosphate which is analogous to a triphosphate as tenofovir itself already has one phosphonate residue the active compound that inhibits reverse transcriptase via chain termination 13 14 In fasting persons bioavailability is 25 and highest blood plasma concentrations are reached after one hour 14 When taken with fatty food highest plasma concentrations are reached after two hours and the area under the curve is increased by 40 14 It is an inhibitor of cytochrome P450 1A2 15 Tenofovir is mainly excreted via the kidneys both by glomerular filtration and by tubular secretion using the transport proteins OAT1 OAT3 and ABCC4 13 Detection in body fluids Edit Tenofovir may be measured in plasma by liquid chromatography Such testing is useful for monitoring therapy and to prevent drug accumulation and toxicity in people with kidney or liver problems 16 17 18 Chemistry EditTenofovir is a derivative of adenine and this was the chemical starting point for its first published synthesis 19 which was included in patents to the compound 20 During drug development attention switched to the phosphonate ester derivative tenofovir disoproxil which was the subject of extensive process chemistry to provide a viable manufacturing route Adenine is first reacted with a chiral version of propylene carbonate with R absolute configuration using sodium hydroxide as base Under these conditions the reaction is regioselective with alkylation occurring exclusively in the imidazole ring and at the less hindered carbon of the dioxolane In the second step the hydroxyl group is reacted with a phosphonic acid derivative using tert butyllithium as base to ensure selective O alkylation with the formation of an ether bond Tenofovir is formed when the diethyl phosphonate group is converted to its acid using trimethylsilyl chloride in the presence of sodium bromide a further refinement of the original manufacturing route 21 22 23 The synthesis of the alternative ester in tenofovir disoproxil is completed by alkylation with the appropriate chloromethyl ether derivative and this may be purified as its fumarate salt 21 History EditTenofovir was initially synthesized by Antonin Holy at the Institute of Organic Chemistry and Biochemistry of the Czechoslovak Academy of Sciences in Prague The patent filed in 1986 makes no mention of the potential use of the compound for the treatment of HIV infection but claims activity against herpes simplex virus 20 In 1985 De Clercq and Holy described the activity of PMPA against HIV in cell culture 24 Shortly thereafter a collaboration with the biotechnology company Gilead Sciences led to the investigation of PMPA s potential as a treatment for HIV infected patients In 1997 researchers from Gilead and the University of California San Francisco demonstrated that tenofovir exhibits anti HIV effects in humans when dosed by subcutaneous injection 25 The initial form of tenofovir used in these studies had limited potential for widespread use because it poorly penetrated cells and was not absorbed when given by mouth Gilead developed a pro drug version of tenofovir tenofovir disoproxil This version of tenofovir is often referred to simply as tenofovir In this version of the drug the two negative charges of the tenofovir phosphonic acid group are masked thus enhancing oral absorption Tenofovir disoproxil was approved in the U S in 2001 for the treatment of HIV and in 2008 for the treatment of chronic hepatitis B 26 27 Drug forms EditTenofovir disoproxil can be taken by mouth and is sold under the brand name Viread among others 28 Tenofovir disoproxil is a pro drug form of tenofovir phosphonate which is liberated intracellularly and converted to tenofovir disphophate 29 It is marketed by Gilead Sciences as the fumarate abbreviated TDF 30 Tenofovir disoproxil is also available in pills which combine a number of antiviral drugs into a single dose Well known combinations include Atripla tenofovir disoproxil emtricitabine efavirenz Complera tenofovir disoproxil emtricitabine rilpivirine Stribild tenofovir disoproxil emtricitabine elvitegravir cobicistat and Truvada tenofovir disoproxil emtricitabine 28 Gilead has created a second pro drug form of the active drug tenofovir diphosphate called tenofovir alafenamide It differs from tenofovir disoproxil due to its activation in the lymphoid cells This allows the active metabolites to accumulate in those cells leading to lower systemic exposure and potential toxicities 10 References Edit a b c d e f g h i j k Tenofovir Disoproxil Fumarate The American Society of Health System Pharmacists Archived from the original on 30 November 2016 Retrieved 29 November 2016 Stribild PubChem U S National Library of Medicine Retrieved 6 February 2022 Martin P Lau DT Nguyen MH Janssen HL Dieterich DT Peters MG Jacobson IM November 2015 A Treatment Algorithm for the Management of Chronic Hepatitis B Virus Infection in the United States 2015 Update Clinical Gastroenterology and Hepatology 13 12 2071 87 e16 doi 10 1016 j cgh 2015 07 007 PMID 26188135 Fischer J Ganellin CR 2006 Analogue based Drug Discovery John Wiley amp Sons p 505 ISBN 9783527607495 Archived from the original on 2017 09 08 World Health Organization 2019 World Health Organization model list of essential medicines 21st list 2019 Geneva World Health Organization hdl 10665 325771 WHO MVP EMP IAU 2019 06 License CC BY NC SA 3 0 IGO Teva Announces Exclusive Launch of a Generic version of Viread in the United States www tevapharm com Archived from the original on 2018 11 06 Retrieved 2018 11 06 a b c d e Tenofovirdisoproxil Prescribing Information PDF Gilead Sciences Inc November 2012 Archived from the original PDF on 7 February 2013 Okwundu CI Uthman OA Okoromah CA July 2012 Antiretroviral pre exposure prophylaxis PrEP for preventing HIV in high risk individuals The Cochrane Database of Systematic Reviews 7 7 CD007189 doi 10 1002 14651858 CD007189 pub3 PMID 22786505 Bourke E 14 June 2013 Preventive drug could reduce HIV transmission among injecting drug users The Conversation Australia The Conversation Media Group Archived from the original on 1 November 2013 Retrieved 17 June 2013 a b c d Ustianowski A Arends JE June 2015 Tenofovir What We Have Learnt After 7 5 Million Person Years of Use Infectious Diseases and Therapy 4 2 145 57 doi 10 1007 s40121 015 0070 1 PMC 4471058 PMID 26032649 Tenofovir MedlinePlus Drug Information MedlineP U S National Library of Medicine Archived from the original on 2016 11 10 Retrieved 2016 11 09 Morlat P Vivot A Vandenhende MA Dauchy FA Asselineau J Deti E Gerard Y Lazaro E Duffau P Neau D Bonnet F Chene G 2013 06 12 Role of traditional risk factors and antiretroviral drugs in the incidence of chronic kidney disease ANRS CO3 Aquitaine cohort France 2004 2012 PLOS ONE 8 6 e66223 Bibcode 2013PLoSO 866223M doi 10 1371 journal pone 0066223 PMC 3680439 PMID 23776637 a b c Haberfeld H ed 2015 Austria Codex in German Vienna Osterreichischer Apothekerverlag a b c d e f g Tenofovir DrugBank Archived from the original on 8 September 2015 Tenofovir disoproxil Pubchem U S National Library of Medicine Retrieved 2018 04 17 Delahunty T Bushman L Robbins B Fletcher CV July 2009 The simultaneous assay of tenofovir and emtricitabine in plasma using LC MS MS and isotopically labeled internal standards Journal of Chromatography B 877 20 21 1907 14 doi 10 1016 j jchromb 2009 05 029 PMC 2714254 PMID 19493710 Kearney BP Yale K Shah J Zhong L Flaherty JF 2006 Pharmacokinetics and dosing recommendations of tenofovir disoproxil fumarate in hepatic or renal impairment Clinical Pharmacokinetics 45 11 1115 24 doi 10 2165 00003088 200645110 00005 PMID 17048975 S2CID 6322957 Baselt R 2008 Disposition of Toxic Drugs and Chemicals in Man 8th ed Foster City California Biomedical Publications pp 1490 1492 Holy A Rosenberg I 1982 Preparation of 5 O phosphonylmethyl analogues of nucleoside 5 phosphates 5 diphosphates and 5 triphosphates Collection of Czechoslovak Chemical Communications 47 12 3447 3463 doi 10 1135 cccc19823447 a b US patent 4808716 Holy A Rosenberg I 9 phosponylmethoxyalkyl adenines the method of preparation and utilization thereof published 1989 02 28 assigned to Czech Academy of Sciences a b Brown Ripin DH Teager DS Fortunak J Basha SM Bivins N Boddy CN et al 2010 Process Improvements for the Manufacture of Tenofovir Disoproxil Fumarate at Commercial Scale Organic Process Research amp Development 14 5 1194 1201 doi 10 1021 op1001337 Houghton SR Melton J Fortunak J Brown Ripin DH Boddy CN 2010 Rapid mild method for phosphonate diester hydrolysis Development of a one pot synthesis of tenofovir disoproxil fumarate from tenofovir diethyl ester Tetrahedron 66 41 8137 8144 doi 10 1016 j tet 2010 08 037 Vardanyan R Hruby V 2016 34 Antiviral Drugs Synthesis of Best Seller Drugs pp 714 716 doi 10 1016 B978 0 12 411492 0 00034 1 ISBN 9780124114920 S2CID 75449475 US 4724233 De Clercq E Holy A Rosenberg I Therapeutical application of phosphonylmethoxyalkyl adenines Deeks SG Barditch Crovo P Lietman PS Hwang F Cundy KC Rooney JF Hellmann NS Safrin S Kahn JO September 1998 Safety pharmacokinetics and antiretroviral activity of intravenous 9 2 R Phosphonomethoxy propyl adenine a novel anti human immunodeficiency virus HIV therapy in HIV infected adults Antimicrobial Agents and Chemotherapy 42 9 2380 4 doi 10 1128 aac 42 9 2380 PMC 105837 PMID 9736567 Shwiff K FDA letter of approval regarding treatment of hepatitis B PDF Food and Drug Administration Archived from the original PDF on 25 February 2009 Shwiff Kathy 11 August 2008 FDA Clears Viread for Hepatitis B The Wall Street Journal Dow Jones amp Company Inc Archived from the original on 8 September 2017 a b Drugs FDA FDA Approved Drug Products www accessdata fda gov Archived from the original on 2016 11 10 Retrieved 2016 11 09 Mouton JP Cohen K Maartens G November 2016 Key toxicity issues with the WHO recommended first line antiretroviral therapy regimen Expert Review of Clinical Pharmacology 9 11 1493 1503 doi 10 1080 17512433 2016 1221760 PMID 27498720 S2CID 205930751 Emau P Jiang Y Agy MB Tian B Bekele G Tsai CC November 2006 Post exposure prophylaxis for SIV revisited animal model for HIV prevention AIDS Research and Therapy 3 29 doi 10 1186 1742 6405 3 29 PMC 1687192 PMID 17132170 External links Edit Tenofovir disoproxil Drug Information Portal U S National Library of Medicine Tenofovir disoproxil fumarate Drug Information Portal U S National Library of Medicine Portals Medicine Viruses Retrieved from https en wikipedia org w index php title Tenofovir disoproxil amp oldid 1167447686, wikipedia, wiki, book, books, library,

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