Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Abacavir: Difference between pages
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Saving copy of the {{drugbox}} taken from revid 474113703 of page Abacavir for the Chem/Drugbox validation project (updated: 'DrugBank'). |
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{{short description|Chemical compound}} |
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{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid [{{fullurl:Abacavir|oldid=474113703}} 474113703] of page [[Abacavir]] with values updated to verified values.}} |
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{{Use dmy dates|date=September 2019}} |
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{{Drugbox |
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{{Infobox drug |
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| Verifiedfields = changed |
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| Watchedfields = changed |
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| verifiedrevid = 456663180 |
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| verifiedrevid = 477236809 |
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| IUPAC_name = {(1''S'',4''R'')-4-[2-amino-6-(cyclopropylamino)-9''H''-purin-9-yl]cyclopent-2-en-1-yl}methanol |
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| image = Abacavir. |
| image = Abacavir.svg |
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| width = 200 |
| width = 200 |
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| alt = |
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| image2 = Abacavir_3d_structure.png |
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| image2 = Abacavir ball-and-stick model.png |
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| caption = Chemical structure of abacavir |
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| alt2 = |
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| caption = Chemical structure of abacavir |
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| USAN = Abacavir sulfate |
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<!--Clinical data--> |
<!-- Clinical data --> |
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| pronounce = {{IPAc-en|audio=en-abacavir.ogg|ə|ˈ|b|æ|k|ə|v|ɪər}} |
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| tradename = Ziagen |
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| tradename = Ziagen |
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| Drugs.com = {{drugs.com|monograph|abacavir-sulfate}} |
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| Drugs.com = {{drugs.com|monograph|abacavir}} |
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| MedlinePlus = a699012 |
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| MedlinePlus = a699012 |
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| pregnancy_AU = B3 |
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| licence_EU = yes |
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| pregnancy_US = C |
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| DailyMedID = Abacavir |
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| legal_UK = POM |
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| pregnancy_AU = B3 |
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| routes_of_administration = Oral (solution or tablets) |
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| pregnancy_AU_comment = |
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| pregnancy_category = |
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| routes_of_administration = [[Oral administration|By mouth]] |
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| class = |
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| ATC_prefix = J05 |
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| ATC_suffix = AF06 |
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| ATC_supplemental = |
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<!-- |
<!-- Legal status --> |
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| legal_AU = S4 |
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| bioavailability = 83% |
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| legal_AU_comment = <ref>{{Cite web |url=http://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2011-PI-01963-3 |title=TGA eBS - Product and Consumer Medicine Information Licence |access-date=23 August 2022 |archive-date=24 March 2022 |archive-url=https://web.archive.org/web/20220324155412/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2011-PI-01963-3 |url-status=live }}</ref> |
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| metabolism = [[Liver|Hepatic]] |
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| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F --> |
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| legal_BR_comment = |
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| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII --> |
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| legal_CA_comment = |
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| legal_DE = <!-- Anlage I, II, III or Unscheduled --> |
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| legal_DE_comment = |
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| legal_NZ = <!-- Class A, B, C --> |
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| legal_NZ_comment = |
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| legal_UK = POM |
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| legal_UK_comment = |
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| legal_US = Rx-only |
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| legal_US_comment = <ref name="Ziagen FDA label" /> |
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| legal_EU = Rx-only |
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| legal_EU_comment = <ref name="Ziagen EPAR">{{cite web | title=Ziagen EPAR | website=European Medicines Agency | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/ziagen | access-date=22 August 2022 | archive-date=30 July 2022 | archive-url=https://web.archive.org/web/20220730022026/https://www.ema.europa.eu/en/medicines/human/EPAR/ziagen | url-status=live }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref> |
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| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV --> |
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| legal_UN_comment = |
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| legal_status = <!-- For countries not listed above --> |
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<!-- Pharmacokinetic data --> |
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| bioavailability = 83% |
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| protein_bound = |
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| metabolism = [[Liver]] |
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| metabolites = |
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| onset = |
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| elimination_half-life = 1.54 ± 0.63 h |
| elimination_half-life = 1.54 ± 0.63 h |
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| duration_of_action = |
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| excretion = [[Kidney|Renal]] (1.2% abacavir, 30% 5'-carboxylic acid metabolite, 36% 5'-glucuronide metabolite, 15% unidentified minor metabolites). Fecal (16%) |
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| excretion = [[Kidney]] (1.2% abacavir, 30% 5'-carboxylic acid metabolite, 36% 5'-glucuronide metabolite, 15% unidentified minor metabolites). Fecal (16%) |
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<!--Identifiers--> |
<!-- Identifiers --> |
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| |
| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number = 136470-78-5 |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_supplemental = |
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| CAS_number = 136470-78-5 |
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| PubChem = 441300 |
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| ATC_prefix = J05 |
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| IUPHAR_ligand = |
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| ATC_suffix = AF06 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| PubChem = 441300 |
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| DrugBank = DB01048 |
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| DrugBank_Ref = {{drugbankcite|changed|drugbank}} |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| DrugBank = DB01048 |
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| ChemSpiderID = 390063 |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| ChemSpiderID = 390063 |
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| UNII = WR2TIP26VS |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| UNII = WR2TIP26VS |
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| KEGG = D07057 |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| ChEBI_Ref = {{ebicite|correct|EBI}} |
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| KEGG = D07057 |
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| ChEBI = 421707 |
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| ChEBI_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEBI = 421707 |
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| ChEMBL = 1380 |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| NIAID_ChemDB = 028596 |
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| ChEMBL = 1380 |
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| PDB_ligand = |
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| NIAID_ChemDB = 028596 |
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| synonyms = |
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<!--Chemical data--> |
<!-- Chemical and physical data --> |
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| IUPAC_name = {(1''S'',4''R'')-4-[2-amino-6-(cyclopropylamino)-9''H''-purin-9-yl]cyclopent-2-en-1-yl}methanol |
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| C=14 | H=18 | N=6 | O=1 |
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| C = 14 |
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| molecular_weight = 286.332 g/mol |
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| H = 18 |
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| smiles = n3c1c(ncn1[C@H]2/C=C\[C@@H](CO)C2)c(nc3N)NC4CC4 |
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| N = 6 |
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| InChI = 1/C14H18N6O/c15-14-18-12(17-9-2-3-9)11-13(19-14)20(7-16-11)10-4-1-8(5-10)6-21/h1,4,7-10,21H,2-3,5-6H2,(H3,15,17,18,19)/t8-,10+/m1/s1 |
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| O = 1 |
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| InChIKey = MCGSCOLBFJQGHM-SCZZXKLOBP |
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| SMILES = n3c1c(ncn1[C@H]2/C=C\[C@@H](CO)C2)c(nc3N)NC4CC4 |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 1S/C14H18N6O/c15-14-18-12(17-9-2-3-9)11-13(19-14)20(7-16-11)10-4-1-8(5-10)6-21/h1,4,7-10,21H,2-3,5-6H2,(H3,15,17,18,19)/t8-,10+/m1/s1 |
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| StdInChI = 1S/C14H18N6O/c15-14-18-12(17-9-2-3-9)11-13(19-14)20(7-16-11)10-4-1-8(5-10)6-21/h1,4,7-10,21H,2-3,5-6H2,(H3,15,17,18,19)/t8-,10+/m1/s1 |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI_comment = |
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| StdInChIKey = MCGSCOLBFJQGHM-SCZZXKLOSA-N |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey = MCGSCOLBFJQGHM-SCZZXKLOSA-N |
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| density = |
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| density_notes = |
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| melting_point = 165 |
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| melting_high = |
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| melting_notes = |
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| boiling_point = |
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| boiling_notes = |
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| solubility = |
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| sol_units = |
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| specific_rotation = |
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}} |
}} |
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<!-- Definition and uses --> |
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'''Abacavir''', sold under the brand name '''Ziagen''' among others, is a [[medication]] used to treat [[HIV/AIDS]].<ref name="Ziagen FDA label" /><ref name="Ziagen EPAR" /><ref name=AHFS2015>{{cite web|title=Abacavir Sulfate|url=https://www.drugs.com/monograph/abacavir-sulfate.html|publisher=The American Society of Health-System Pharmacists|access-date=31 July 2015|url-status=live|archive-url=https://web.archive.org/web/20170821211053/https://www.drugs.com/monograph/abacavir-sulfate.html|archive-date=21 August 2017|df=dmy-all }}</ref><ref>{{cite web|url=https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/292/drug-name-abbreviations|title=Drug Name Abbreviations Adult and Adolescent ARV Guidelines|website=AIDSinfo|access-date=2016-11-08|url-status=live|archive-url=https://web.archive.org/web/20161109083720/https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/292/drug-name-abbreviations|archive-date=2016-11-09|df=dmy-all }}</ref> Similar to other [[nucleoside analog]] [[reverse-transcriptase inhibitor]]s (NRTIs), abacavir is used together with other [[HIV medications]], and is not recommended by itself.<ref>{{cite web|url=https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/12/what-not-to-use|title=What Not to Use Adult and Adolescent ARV Guidelines|website=AIDSinfo|access-date=2016-11-08|url-status=live|archive-url=https://web.archive.org/web/20161109021833/https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/12/what-not-to-use|archive-date=2016-11-09|df=dmy-all }}</ref> It is taken by mouth as a tablet or solution and may be used in children over the age of three months.<ref name=AHFS2015/><ref name=Yu2008/> |
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<!-- Side effects and mechanism --> |
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Abacavir is generally well tolerated.<ref name=Yu2008/> Common side effects include vomiting, [[insomnia]] (trouble sleeping), fever, and feeling tired.<ref name=AHFS2015/> Other common side effects include loss of appetite, headache, nausea (feeling sick), diarrhea, rash, and lethargy (lack of energy).<ref name="Ziagen EPAR" /> More severe side effects include [[hypersensitivity]], [[liver damage]], and [[lactic acidosis]].<ref name=AHFS2015/> [[Genetic testing]] can indicate whether a person is at higher risk of developing hypersensitivity.<ref name=AHFS2015/> Symptoms of hypersensitivity include rash, vomiting, and shortness of breath.<ref name=Yu2008>{{cite journal | vauthors = Yuen GJ, Weller S, Pakes GE | title = A review of the pharmacokinetics of abacavir | journal = Clinical Pharmacokinetics | volume = 47 | issue = 6 | pages = 351–371 | date = 2008 | pmid = 18479171 | doi = 10.2165/00003088-200847060-00001 | s2cid = 31107341 }}</ref> Abacavir is in the NRTI class of medications, which work by blocking [[reverse transcriptase]], an enzyme needed for [[HIV virus]] [[viral replication|replication]].<ref name=Gov2016>{{cite web|url=http://www.hiv.va.gov/patient/treat/NRTIs.asp|title=Nucleoside reverse transcriptase inhibitors (NRTIs or 'nukes') - HIV/AIDS|website=www.hiv.va.gov|access-date=2016-11-08|url-status=live|archive-url=https://web.archive.org/web/20161109083725/http://www.hiv.va.gov/patient/treat/NRTIs.asp|archive-date=2016-11-09|df=dmy-all }}</ref> Within the NRTI class, abacavir is a [[carbocyclic nucleoside]].<ref name=AHFS2015/> |
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<!-- History and culture --> |
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Abacavir was patented in 1988, and approved for use in the United States in 1998.<ref>{{cite book| vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery|date=2006|publisher=John Wiley & Sons|isbn=9783527607495|page=505|url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA505|url-status=live|archive-url=https://web.archive.org/web/20170908213935/https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA505|archive-date=2017-09-08|df=dmy-all }}</ref><ref>{{cite book| vauthors = Kane BM |title=HIV/AIDS Treatment Drugs|date=2008|publisher=Infobase Publishing|isbn=9781438102078|page=56|url=https://books.google.com/books?id=RFNVvStUJlkC&pg=PA56|url-status=live|archive-url=https://web.archive.org/web/20170908213935/https://books.google.com/books?id=RFNVvStUJlkC&pg=PA56|archive-date=2017-09-08|df=dmy-all }}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> It is available as a [[generic medication]].<ref name=AHFS2015/> Abacavir is used together with other HIV medications, such as [[abacavir/lamivudine/zidovudine]], [[abacavir/dolutegravir/lamivudine]], and [[abacavir/lamivudine]].<ref name=Yu2008/><ref name=Gov2016/> The combination abacavir/lamivudine is an essential medicine.<ref name=WHO21st/> |
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==Medical uses== |
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Abacavir, in combination with other antiretroviral agents, is [[indicated]] for the treatment of HIV-1 infection.<ref name="Ziagen FDA label" /><ref name="Ziagen EPAR" /> Abacavir should be used in combination with other antiretroviral agents.<ref name="Ziagen FDA label" /><ref name="Ziagen EPAR" /> |
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== Contraindications == |
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Abacavir is contraindicated for people who have the HLA‑B*5701 allele or who have moderate or severe [[liver disease]] (hepatic impairment).<ref name="Ziagen FDA label" /><ref name="Ziagen EPAR" /> |
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==Side effects== |
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Common adverse reactions include [[nausea]], [[headache]], [[fatigue]], [[vomiting]], [[diarrhea]], [[Anorexia (symptom)]] (loss of appetite), and [[insomnia]] (trouble sleeping). Rare but serious side effects include [[hypersensitivity]] reaction such as [[rash]], elevated [[AST/ALT ratio|AST and ALT]], [[Depression (mood)|depression]], [[anxiety]], [[fever]]/[[chills]], URI, [[lactic acidosis]], [[hypertriglyceridemia]], and [[lipodystrophy]].<ref>{{cite web|url=https://online.epocrates.com/noFrame/showPage.do?method=drugs&MonographId=2043&ActiveSectionId=5|title=Abacavir Adverse Reactions|website=Epocrates Online|access-date=9 November 2012|archive-date=23 August 2021|archive-url=https://web.archive.org/web/20210823111013/https://online.epocrates.com/noFrame/showPage.do?method=drugs&MonographId=2043&ActiveSectionId=5|url-status=live}}</ref> |
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===Hypersensitivity syndrome=== |
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[[Hypersensitivity]] to abacavir is strongly associated with a specific allele at the [[human leukocyte antigen]] B [[locus (genetics)|locus]] namely [[HLA-B57|HLA-B*5701]].<ref>{{cite journal | vauthors = Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, Jägel-Guedes E, Rugina S, Kozyrev O, Cid JF, Hay P, Nolan D, Hughes S, Hughes A, Ryan S, Fitch N, Thorborn D, Benbow A | display-authors = 6 | title = HLA-B*5701 screening for hypersensitivity to abacavir | journal = The New England Journal of Medicine | volume = 358 | issue = 6 | pages = 568–579 | date = February 2008 | pmid = 18256392 | doi = 10.1056/nejmoa0706135 | url = http://researchrepository.murdoch.edu.au/id/eprint/8930/ | access-date = 9 July 2019 | archive-date = 22 January 2021 | archive-url = https://web.archive.org/web/20210122042920/https://researchrepository.murdoch.edu.au/id/eprint/8930/ | url-status = live | doi-access = free }}</ref><ref>{{cite journal | vauthors = Rauch A, Nolan D, Martin A, McKinnon E, Almeida C, Mallal S | title = Prospective genetic screening decreases the incidence of abacavir hypersensitivity reactions in the Western Australian HIV cohort study | journal = Clinical Infectious Diseases | volume = 43 | issue = 1 | pages = 99–102 | date = July 2006 | pmid = 16758424 | doi = 10.1086/504874 | doi-access = free }}</ref><ref>{{cite book | title=Medical Genetics Summaries | chapter=Abacavir Therapy and HLA-B*57:01 Genotype | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK315783/ | veditors=Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, Malheiro AJ | display-editors=3 | publisher=[[National Center for Biotechnology Information]] (NCBI) | year=2015 | pmid=28520363 | id=Bookshelf ID: NBK315783 | vauthors=Dean L | url=https://www.ncbi.nlm.nih.gov/books/NBK61999/ | access-date=2019-01-14 | archive-date=26 October 2020 | archive-url=https://web.archive.org/web/20201026145821/https://www.ncbi.nlm.nih.gov/books/NBK61999/ | url-status=live }}</ref> The mechanism for this hypersensitivity reaction is due to abacavir binding in the [[antigen]]-binding cleft of HLA-B*57:01, allowing alternative [[peptide]]s to bind, which appear as "non-self" when presented to [[T cell]]s.<ref name="Immune self-reactivity triggered by">{{cite journal | vauthors = Illing PT, Vivian JP, Dudek NL, Kostenko L, Chen Z, Bharadwaj M, Miles JJ, Kjer-Nielsen L, Gras S, Williamson NA, Burrows SR, Purcell AW, Rossjohn J, McCluskey J | display-authors = 6 | title = Immune self-reactivity triggered by drug-modified HLA-peptide repertoire | journal = Nature | volume = 486 | issue = 7404 | pages = 554–558 | date = June 2012 | pmid = 22722860 | doi = 10.1038/nature11147 | s2cid = 4408811 | bibcode = 2012Natur.486..554I | doi-access = free }}</ref> There is an association between the prevalence of HLA-B*5701 and ancestry. The prevalence of the [[allele]] is estimated to be 3.4 to 5.8 percent on average in populations of European ancestry, 17.6 percent in [[Indian American]]s, 3.0 percent in Hispanic Americans, and 1.2 percent in [[Chinese American]]s.<ref>{{cite journal | vauthors = Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses AD | display-authors = 6 | title = Genetic variations in HLA-B region and hypersensitivity reactions to abacavir | journal = Lancet | volume = 359 | issue = 9312 | pages = 1121–1122 | date = March 2002 | pmid = 11943262 | doi = 10.1016/s0140-6736(02)08158-8 | s2cid = 9434238 }}</ref><ref>{{cite journal | vauthors = Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte C, Maxwell D, James I, Christiansen FT | display-authors = 6 | title = Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir | journal = Lancet | volume = 359 | issue = 9308 | pages = 727–732 | date = March 2002 | pmid = 11888582 | doi = 10.1016/s0140-6736(02)07873-x | s2cid = 12923232 }}</ref> There is significant variability in the prevalence of HLA-B*5701 among African populations. In [[African American]]s, the prevalence is estimated to be 1.0 percent on average, 0 percent in the [[Yoruba people|Yoruba]] from [[Nigeria]], 3.3 percent in the [[Luhya people|Luhya]] from [[Kenya]], and 13.6 percent in the [[Masai people|Masai]] from Kenya, although the average values are derived from highly variable frequencies within sample groups.<ref>{{cite journal | vauthors = Rotimi CN, Jorde LB | title = Ancestry and disease in the age of genomic medicine | journal = The New England Journal of Medicine | volume = 363 | issue = 16 | pages = 1551–1558 | date = October 2010 | pmid = 20942671 | doi = 10.1056/nejmra0911564 | doi-access = free }}</ref> |
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Common symptoms of abacavir hypersensitivity syndrome include [[fever]], [[malaise]], [[nausea]], and [[diarrhea]]. Some patients may also develop a [[rash|skin rash]].<ref>{{cite journal | vauthors = Phillips E, Mallal S | title = Successful translation of pharmacogenetics into the clinic: the abacavir example | journal = Molecular Diagnosis & Therapy | volume = 13 | issue = 1 | pages = 1–9 | year = 2009 | pmid = 19351209 | doi = 10.1007/bf03256308 | s2cid = 45896364 }}</ref> Symptoms of AHS typically manifest within six weeks of treatment using abacavir, although they may be confused with symptoms of [[HIV]], [[immune reconstitution syndrome]], hypersensitivity syndromes associated with other drugs, or infection.<ref>{{cite journal | vauthors = Phillips E, Mallal S | title = Drug hypersensitivity in HIV | journal = Current Opinion in Allergy and Clinical Immunology | volume = 7 | issue = 4 | pages = 324–330 | date = August 2007 | pmid = 17620824 | doi = 10.1097/aci.0b013e32825ea68a | s2cid = 37549824 }}</ref> The U.S. [[Food and Drug Administration]] (FDA) released an alert concerning abacavir and abacavir-containing medications on 24 July 2008,<ref>{{cite web|url=https://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm123927.htm|title=Information for Healthcare Professionals: Abacavir (marketed as Ziagen) and Abacavir-Containing Medications|date=2008-07-24|publisher=[[Food and Drug Administration]] (FDA) |archive-url=https://web.archive.org/web/20131211024108/https://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm123927.htm|archive-date=2013-12-11|url-status=dead|access-date=2013-11-29|df=dmy-all }}</ref> and the FDA-approved drug label for abacavir recommends pre-therapy screening for the HLA-B*5701 allele and the use of alternative therapy in subjects with this allele.<ref name="Ziagen FDA label">{{cite web |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ca73b519-015a-436d-aa3c-af53492825a1 |title=Ziagen- abacavir sulfate tablet, film coated label |date=30 September 2015 |publisher=[[DailyMed]] |access-date=2019-09-09 |url-status=live |archive-url=https://web.archive.org/web/20170111183846/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ca73b519-015a-436d-aa3c-af53492825a1 |archive-date=2017-01-11 |df=dmy-all }}</ref> Additionally, both the Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenetics Working Group recommend use of an alternative therapy in individuals with the HLA-B*5701 allele.<ref>{{cite journal | vauthors = Swen JJ, Nijenhuis M, de Boer A, Grandia L, Maitland-van der Zee AH, Mulder H, Rongen GA, van Schaik RH, Schalekamp T, Touw DJ, van der Weide J, Wilffert B, Deneer VH, Guchelaar HJ | display-authors = 6 | title = Pharmacogenetics: from bench to byte--an update of guidelines | journal = Clinical Pharmacology and Therapeutics | volume = 89 | issue = 5 | pages = 662–673 | date = May 2011 | pmid = 21412232 | doi = 10.1038/clpt.2011.34 | s2cid = 2475005 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Martin MA, Hoffman JM, Freimuth RR, Klein TE, Dong BJ, Pirmohamed M, Hicks JK, Wilkinson MR, Haas DW, Kroetz DL | display-authors = 6 | title = Clinical Pharmacogenetics Implementation Consortium Guidelines for HLA-B Genotype and Abacavir Dosing: 2014 update | journal = Clinical Pharmacology and Therapeutics | volume = 95 | issue = 5 | pages = 499–500 | date = May 2014 | pmid = 24561393 | pmc = 3994233 | doi = 10.1038/clpt.2014.38 }}</ref> |
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[[File:Epikutanni-test.jpg|thumb|[[Patch test]]]] |
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[[Patch test|Skin-patch testing]] may also be used to determine whether an individual will experience a hypersensitivity reaction to abacavir, although some patients susceptible to developing AHS may not react to the patch test.<ref>{{cite journal | vauthors = Shear NH, Milpied B, Bruynzeel DP, Phillips EJ | title = A review of drug patch testing and implications for HIV clinicians | journal = AIDS | volume = 22 | issue = 9 | pages = 999–1007 | date = May 2008 | pmid = 18520343 | doi = 10.1097/qad.0b013e3282f7cb60 | s2cid = 2972984 }}</ref> |
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The development of suspected hypersensitivity reactions to abacavir requires immediate and permanent discontinuation of abacavir therapy in all patients, including patients who do not possess the HLA-B*5701 allele. On 1 March 2011, the FDA informed the public about an ongoing safety review of abacavir and a possible increased risk of heart attack associated with the drug.<ref>{{cite web | title=FDA Drug Safety Communication: Safety Review update of Abacavir and possible increased risk of heart attack | publisher=[[Food and Drug Administration]] (FDA) | date=1 March 2011 | url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-safety-review-update-abacavir-and-possible-increased-risk-heart-attack | access-date=9 September 2019 | archive-date=13 December 2019 | archive-url=https://web.archive.org/web/20191213203739/https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-safety-review-update-abacavir-and-possible-increased-risk-heart-attack | url-status=live }}</ref> A [[meta-analysis]] of 26 studies conducted by the FDA, however, did not find any association between abacavir use and heart attack<ref>{{cite news|url=https://www.drugs.com/fda/abacavir-ongoing-safety-review-possible-increased-risk-heart-attack-12914.html|title=FDA Alert: Abacavir - Ongoing Safety Review: Possible Increased Risk of Heart Attack|work=Drugs.com|access-date=2013-11-29|archive-url=https://web.archive.org/web/20131210144028/http://www.drugs.com/fda/abacavir-ongoing-safety-review-possible-increased-risk-heart-attack-12914.html|archive-date=2013-12-10|url-status=live|df=dmy-all }}</ref><ref>{{cite journal | vauthors = Ding X, Andraca-Carrera E, Cooper C, Miele P, Kornegay C, Soukup M, Marcus KA | title = No association of abacavir use with myocardial infarction: findings of an FDA meta-analysis | journal = Journal of Acquired Immune Deficiency Syndromes | volume = 61 | issue = 4 | pages = 441–447 | date = December 2012 | pmid = 22932321 | doi = 10.1097/QAI.0b013e31826f993c | s2cid = 7997822 | doi-access = free }}</ref> |
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===Immunopathogenesis=== |
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The mechanism underlying abacavir hypersensitivity syndrome is related to the change in the HLA-B*5701 [[protein]] product. Abacavir binds with high specificity to the HLA-B*5701 protein, changing the shape and chemistry of the antigen-binding cleft. This results in a change in [[immune tolerance|immunological tolerance]] and the subsequent activation of abacavir-specific [[cytotoxic T cell]]s, which produce a systemic reaction known as abacavir hypersensitivity syndrome.<ref name="Immune self-reactivity triggered by"/> |
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==Interaction== |
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Abacavir, and in general [[reverse-transcriptase inhibitor|NRTIs]], do not undergo hepatic metabolism and therefore have very limited (to none) interaction with the [[Cytochrome P450|CYP]] enzymes and drugs that effect these enzymes. That being said there are still few interactions that can affect the absorption or the availability of abacavir. Below are few of the common established drug and food interaction that can take place during abacavir co-administration: |
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* [[Protease inhibitors]] such as [[tipranavir]] or [[ritonovir]] may decrease the serum concentration of abacavir through induction of [[glucuronidation]]. Abacavir is metabolized by both [[alcohol dehydrogenase]] and glucuronidation.<ref name=":3">Prescribing information. Ziagen (abacavir). Research Triangle Park, NC: GlaxoSmithKline, July 2002</ref><ref>{{cite journal | vauthors = Vourvahis M, Kashuba AD | title = Mechanisms of pharmacokinetic and pharmacodynamic drug interactions associated with ritonavir-enhanced tipranavir | journal = Pharmacotherapy | volume = 27 | issue = 6 | pages = 888–909 | date = June 2007 | pmid = 17542771 | doi = 10.1592/phco.27.6.888 | s2cid = 23591048 }}</ref> |
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* [[Ethanol]] may result in increased levels of abacavir through the inhibition of alcohol dehydrogenase. Abacavir is metabolized by both alcohol dehydrogenase and glucuronidation.<ref name=":3"/><ref>{{cite journal | vauthors = McDowell JA, Chittick GE, Stevens CP, Edwards KD, Stein DS | title = Pharmacokinetic interaction of abacavir (1592U89) and ethanol in human immunodeficiency virus-infected adults | journal = Antimicrobial Agents and Chemotherapy | volume = 44 | issue = 6 | pages = 1686–1690 | date = June 2000 | pmid = 10817729 | pmc = 89933 | doi = 10.1128/aac.44.6.1686-1690.2000 }}</ref> |
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* [[Methadone]] may diminish the therapeutic effect of Abacavir. Abacavir may decrease the serum concentration of Methadone.<ref>{{cite journal | vauthors = Berenguer J, Pérez-Elías MJ, Bellón JM, Knobel H, Rivas-González P, Gatell JM, Miguélez M, Hernández-Quero J, Flores J, Soriano V, Santos I, Podzamczer D, Sala M, Camba M, Resino S | display-authors = 6 | title = Effectiveness and safety of abacavir, lamivudine, and zidovudine in antiretroviral therapy-naive HIV-infected patients: results from a large multicenter observational cohort | journal = Journal of Acquired Immune Deficiency Syndromes | volume = 41 | issue = 2 | pages = 154–159 | date = February 2006 | pmid = 16394846 | doi = 10.1097/01.qai.0000194231.08207.8a | s2cid = 17609676 | doi-access = free }}</ref><ref>Dolophine(methadone) [prescribing information]. Columbus, OH: Roxane Laboratories, Inc.; March 2015.</ref> |
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* [[Orlistat]] may decrease the serum concentration of antiretroviral drugs. The mechanism of this interaction is not fully established but it is suspected that it is due to the decreased absorption of abacavir by orlistat.<ref>{{cite journal | vauthors = Gervasoni C, Cattaneo D, Di Cristo V, Castoldi S, Gervasi E, Clementi E, Riva A | title = Orlistat: weight lost at cost of HIV rebound | journal = The Journal of Antimicrobial Chemotherapy | volume = 71 | issue = 6 | pages = 1739–1741 | date = June 2016 | pmid = 26945709 | doi = 10.1093/jac/dkw033 | doi-access = free }}</ref> |
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* [[Cabozantinib]]: Drugs from the [[Multidrug resistance-associated protein 2|MRP2 inhibitor]] (Multidrug resistance-associated protein 2 inhibitors) family such as abacavir could increase the serum concentration of Cabozantinib.<ref>Cometriq (cabozantinib) [prescribing information]. South San Francisco, CA: Exelixis, Inc.; May 2016.</ref> |
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==Mechanism of action== |
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Abacavir is a [[nucleoside reverse transcriptase inhibitor]] that inhibits [[viral replication]]. It is a [[guanosine]] analogue that is phosphorylated to carbovir triphosphate (CBV-TP). CBV-TP competes with the viral molecules and is incorporated into the viral [[DNA]]. Once CBV-TP is integrated into the viral DNA, [[transcription (genetics)|transcription]] and HIV [[reverse transcriptase]] is inhibited.<ref name=":2">Product Information: ZIAGEN(R) oral tablets, oral solution, abacavir sulfate oral tablets, oral solution. ViiV Healthcare (per Manufacturer), Research Triangle Park, NC, 2015.</ref> |
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==Pharmacokinetics== |
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Abacavir is given orally and is rapidly absorbed with a high [[bioavailability]] of 83%.<ref name="Chittick_1999">{{cite journal | vauthors = Chittick GE, Gillotin C, McDowell JA, Lou Y, Edwards KD, Prince WT, Stein DS | title = Abacavir: absolute bioavailability, bioequivalence of three oral formulations, and effect of food | journal = Pharmacotherapy | volume = 19 | issue = 8 | pages = 932–942 | date = August 1999 | pmid = 10453964 | doi = 10.1592/phco.19.11.932.31568 | s2cid = 20131476 }}</ref> Solution and tablet have comparable concentrations and bioavailability. Abacavir can be taken with or without food.<ref>{{cite web | vauthors = Jones A | url = https://www.aidsmap.com/about-hiv/food-requirements-anti-hiv-medications | title = Food requirements for anti-HIV medications | date = May 2019 | work = aidsmap.com | access-date = 21 December 2020 | archive-date = 25 April 2021 | archive-url = https://web.archive.org/web/20210425215944/https://www.aidsmap.com/about-hiv/food-requirements-anti-hiv-medications | url-status = live }}</ref> |
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Abacavir can cross the [[blood–brain barrier]]. Abacavir is metabolized primarily through the enzymes [[alcohol dehydrogenase]] and [[glucuronosyltransferase|glucuronyl transferase]] to an inactive [[carboxylate]] and [[glucuronide]] metabolites. It has a [[half-life]] of approximately 1.5-2.0 hours. If a person has [[liver failure]], abacavir's half life is increased by 58%.<ref name="pmid15736035">{{cite journal | vauthors = Wyles DL, Gerber JG | title = Abacavir pharmacokinetics in hepatic dysfunction | journal = Clinical Infectious Diseases | volume = 40 | issue = 6 | pages = 909–910 | date = March 2005 | pmid = 15736035 | doi = 10.1086/429247 | doi-access = free }}</ref> |
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Abacavir is eliminated via excretion in the urine (83%) and feces (16%).<ref name="Yuen_2008">{{cite journal | vauthors = Yuen GJ, Weller S, Pakes GE | title = A review of the pharmacokinetics of abacavir | journal = Clinical Pharmacokinetics | volume = 47 | issue = 6 | pages = 351–71 | date = 2008 | pmid = 18479171 | doi = 10.2165/00003088-200847060-00001 | s2cid = 31107341 }}</ref> It is unclear whether abacavir can be removed by [[hemodialysis]] or [[peritoneal dialysis]].<ref name=":2"/> |
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==History== |
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[[Robert Vince (scientist)|Robert Vince]] and Susan Daluge along with Mei Hua, a visiting scientist from China, developed the medication in the '80s.<ref>{{cite web|title=Dr. Robert Vince - 2010 Inductee|url=http://www.minnesotainventors.org/inductees/robert-vince.html|publisher=Minnesota Inventors Hall of Fame|access-date=10 February 2016|url-status=dead|archive-url=https://web.archive.org/web/20160215215827/http://www.minnesotainventors.org/inductees/robert-vince.html|archive-date=15 February 2016|df=dmy-all}}</ref><ref>{{cite web|url=http://drugdesign.umn.edu/bio/cdd-faculty-staff/robert-vince|title=Robert Vince, PhD (faculty listing)|publisher=University of Minnesota|url-status=live|archive-url=https://web.archive.org/web/20160217084119/http://drugdesign.umn.edu/bio/cdd-faculty-staff/robert-vince|archive-date=2016-02-17|df=dmy-all }}</ref><ref name="pmid9145874">{{cite journal | vauthors = Daluge SM, Good SS, Faletto MB, Miller WH, St Clair MH, Boone LR, Tisdale M, Parry NR, Reardon JE, Dornsife RE, Averett DR, Krenitsky TA | display-authors = 6 | title = 1592U89, a novel carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity | journal = Antimicrobial Agents and Chemotherapy | volume = 41 | issue = 5 | pages = 1082–1093 | date = May 1997 | pmid = 9145874 | pmc = 163855 | doi = 10.1128/AAC.41.5.1082 }}</ref> |
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Abacavir was approved by the U.S. [[Food and Drug Administration]] (FDA) on 18 December 1998, and is thus the fifteenth approved antiretroviral drug in the United States.<ref>Mary Annette Banach. "[https://books.google.com/books?id=oWxOAQAAMAAJ&q=FDA+December+18,+1998+Abacavir How HIV Clinicians Acquire Representational Fluency: A Case Study of the HIV Resistance Preceptorship] {{Webarchive|url=https://web.archive.org/web/20220823052822/https://books.google.ge/books?id=oWxOAQAAMAAJ&q=FDA+December+18,+1998+Abacavir |date=23 August 2022 }}", ''University of California'', Berkeley, 2003.</ref> |
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==Synthesis== |
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[[File:Abacavir synthesis.png|thumb|700px|center|Abacavir synthesis:<ref>{{cite journal | vauthors = Crimmins MT, King BW | title = An Efficient Asymmetric Approach to Carbocyclic Nucleosides: Asymmetric Synthesis of 1592U89, a Potent Inhibitor of HIV Reverse Transcriptase | journal = The Journal of Organic Chemistry | volume = 61 | issue = 13 | pages = 4192–4193 | date = June 1996 | pmid = 11667311 | doi = 10.1021/jo960708p }}</ref>]] |
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== References == |
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{{Reflist}} |
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== Further reading == |
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{{refbegin}} |
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* {{cite book | title=Medical Genetics Summaries | chapter=Abacavir Therapy and HLA-B*57:01 Genotype | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK315783/ | veditors=Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, Malheiro AJ | display-editors=3 | publisher=[[National Center for Biotechnology Information]] (NCBI) | date=April 2018 | pmid=28520363 | vauthors=Dean L | url=https://www.ncbi.nlm.nih.gov/books/NBK61999/ | access-date=6 February 2020 | archive-date=26 October 2020 | archive-url=https://web.archive.org/web/20201026145821/https://www.ncbi.nlm.nih.gov/books/NBK61999/ | url-status=live }} |
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{{refend}} |
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== External links == |
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{{Commons category}} |
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* {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/rn/136470-78-5 | publisher = U.S. National Library of Medicine| work = Drug Information Portal| title = Abacavir }} |
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* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/abacavir%20sulfate | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Abacavir sulfate }} |
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* [http://www.pharmgkb.org/pathway/PA166104634 Abacavir pathway on PharmGKB] |
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{{Antiretroviral drug}} |
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{{GlaxoSmithKline}} |
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