Dolutegravir

Identification

Summary

Dolutegravir is an antiviral agent used for the treatment of HIV-1 infections in combination with other antiretroviral agents.

Brand Names

Dovato, Juluca, Tivicay, Triumeq

Generic Name

Dolutegravir

DrugBank Accession Number

DB08930

Background

Dolutegravir is an HIV-1 integrase inhibitor that blocks the strand transfer step of the integration of the viral genome into the host cell (INSTI).¹ The effect of this drug has no homology in human host cells, which gives it excellent tolerability and minimal toxicity.¹¹ Dolutegravir was developed by ViiV Healthcare and FDA-approved on August 12, 2013.¹⁶ On November 21, 2017, dolutegravir, in combination with rilpivirine, was approved as part of the first complete treatment regimen with only two drugs for the treatment of adults with HIV-1 named Juluca.¹⁷

Type

Small Molecule

Groups

Approved

Structure

Similar Structures

Weight: Average: 419.3788
Monoisotopic: 419.129277143
Chemical Formula: C₂₀H₁₉F₂N₃O₅

Synonyms

Dolutegravir

External IDs

GSK572
S-349572
S/GSK1349572

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Pharmacology

Indication

Dolutegravir is indicated in combination with other antiretroviral agents for the treatment of patients with HIV-1 infection that comply with the characteristics of being adults or children aged 12 years and older and present at least a weight of 40 kg.⁷ The FDA combination therapy approval of dolutegravir and rilpivirine is indicated for adults with HIV-1 infections whose virus is currently suppressed (< 50 copies/ml) on a stable regimen for at least six months, without history of treatment failure and no known substitutions associated to resistance to any of the two components of the therapy.¹⁷

Dolutegravir is also available in combination with lamivudine and abacavir for the treatment of adult and pediatric patients with HIV-1 who weigh ≥10kg.¹⁹

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Adjunct therapy in treatment of	Human immunodeficiency virus type 1 (hiv-1) infection		••••••••••••	••••••••••• •••••••••	••••••••• •••••••••••• •••••••• •• ••••• • ••• ••••••••• •••••• •••••••• •••••••••••••••	••••••• ••••••• ••• ••••••••••
Adjunct therapy in treatment of	Human immunodeficiency virus type 1 (hiv-1) infection		••••••••••••	••••••••••• •••••••••	•••••••• •• ••••• • ••• ••••••••• •••••	••••••• ••••••• ••• ••••••••••
Adjunct therapy in treatment of	Human immunodeficiency virus type 1 (hiv-1) infection		••••••••••••	•••••	••••••••• •••••	••••••• ••••••• ••• ••••••••••
Adjunct therapy in treatment of	Human immunodeficiency virus type 1 (hiv-1) infection		••••••••••••	•••••	••••••••• •••••••••••	••••••• ••••••• ••• ••••••••••
Used in combination to treat	Human immunodeficiency virus type 1 (hiv-1) infection	Regimen in combination with: Rilpivirine (DB08864)	••••••••••••	•••••	•• ••••••• •• ••••••••• •••••••• •••••• •••••••••••••• •••••••• ••••••••••••• •••••••••• •••••• ••• •••• •••• •• •••••• ••• •••	••••••• ••••••• ••• ••••••••••

Contraindications & Blackbox Warnings

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Pharmacodynamics

HIV-1 infected subjects on dolutegravir monotherapy demonstrated rapid and dose-dependent reduction of antiviral activity with declines of HIV-1 RNA copies per ml. The antiviral response was maintained for 3 to 4 days after the last dose.³ The sustained response obtained in clinical trials indicates that dolutegravir has a tight binding and longer dissociative half-life providing it a high barrier to resistance.¹⁵ The combination therapy (ripivirine and dolutegravir) presented the same viral suppression found in previous three-drug therapies without integrase strand transfer inhibitor mutations or rilpivirine resistance.¹⁸

Mechanism of action

Dolutegravir is an HIV-1 antiviral agent. It inhibits HIV integrase by binding to the active site and blocking the strand transfer step of retroviral DNA integration in the host cell. The strand transfer step is essential in the HIV replication cycle and results in the inhibition of viral activity. Dolutegravir has a mean EC50 value of 0.5 nM (0.21 ng/mL) to 2.1 nM (0.85 ng/mL) in peripheral blood mononuclear cells (PBMCs) and MT-4 cells.⁴

Target	Actions	Organism
AIntegrase	inhibitor	Human immunodeficiency virus 1

Absorption

When 50 mg of dolutegravir once daily was orally administered to HIV-1 infected adults, the AUC, Cmax, and Cmin is 53.6 mcg h/mL, 3.67 mcg/mL, and 1.11 mcg/mL, respectively. The peak plasma concentration was observed 2 to 3 hours post-dose. Steady state is achieved within approximately 5 days with average accumulation ratios for AUC, Cmax, and C24h ranging from 1.2 to 1.5. When 50 mg once daily is given to pediatric patients (12 to < 18 years and weighing ≥40 kg) the Cmax, AUC, and C24 is 3.49 mcg/mL, 46 mcg.h/mL, and 0.90 mcg/mL respectively.¹

Volume of distribution

The administration of a dose of 50 mg of dolutegravir presents an apparent volume of distribution of 17.4 L. The median dolutegravir concentration in CSF was 18 ng/mL after 2 weeks of treatment.¹

Protein binding

Dolutegravir is highly protein bound to human plasma proteins reaching a percentage 98.9% of the administered dose.¹

Metabolism

Dolutegravir is highly metabolized through three main pathways and it forms no long-lived metabolites. The first pathway is defined by the glucuronidation by UGT1A1, the second pathway by carbon oxidation by CYP3A4 and the third pathway is what appears to be a sequential oxidative defluorination and glutathione conjugation. The main metabolite found in blood plasma is the ether glucuronide form (M2) and its chemical properties disrupt its ability to bind metal ions, therefore, it is inactive.¹²

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Dolutegravir

Route of elimination

When a single oral dose of dolutegravir is given, nearly all complete dose is recovered in a proportion of 53% excreted unchanged in the feces and 31% excreted in urine. The renal eliminated recovered dose consists of ether glucuronide of dolutegravir (18.9%), a metabolite formed by oxidation at the benzylic carbon (3.0%), a hydrolytic N-dealkylation product (3.6%) and unchanged drug (< 1%).¹²

Half-life

The half-life of dolutegravir is 14 hours.¹

Clearance

The apparent clearance rate of dultegravir is 1.0 L/h.^Label

Adverse Effects

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Toxicity

Data from an ongoing birth outcome surveillance study has identified an increased risk of neural tube defects when dolutegravir is administered at the time of conception. As defects related to the closure of the neural tube occur from conception through the first 6 weeks of gestation, embryos exposed to dolutegravir from the time of conception through the first 6 weeks of gestation are at potential risk.

Advise adolescents and adults of childbearing potential, including those actively trying to become pregnant, of the potential risk of neural tube defects with the use of TIVICAY and TIVICAY PD. Assess the risks and benefits of TIVICAY and TIVICAY PD and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester. A benefit-risk assessment should consider factors such as the feasibility of switching to another antiretroviral regimen, tolerability, ability to maintain viral suppression, and risk of HIV-1 transmission to the infant against the risk of neural tube defects associated with in-utero dolutegravir exposure during critical periods of fetal development [see Warnings and Precautions (5.3)].

There are insufficient human data on the use of dolutegravir during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. The background risk for major birth defects for the indicated population is unknown. In the U.S. general population, the estimated background rate for major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

In animal reproduction studies, no evidence of adverse developmental outcomes was observed with dolutegravir at systemic exposures (AUC) less than (rabbits) and approximately 27 times (rats) the exposure in humans at the maximum recommended human dose (MRHD) of TIVICAY (see Data).

There is no known specific treatment for an overdose with TIVICAY or TIVICAY PD. If an overdose occurs, the patient should be monitored, and standard supportive treatment applied as required. As dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.

Pathways

Not Available

Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">

Interacting Gene/Enzyme	Allele name	Genotype(s)	Defining Change(s)	Type(s)	Description	Details
UDP-glucuronosyltransferase 1-1	UGT1A1*28 or UGT1A 7/7	Not Available	extra TA in promoter	Effect Directly Studied	Poor drug metabolizer.	Details
UDP-glucuronosyltransferase 1-1	UGT1A1*6	Not Available	G > A	Effect Directly Studied	The presence of this polymorphism in UGT1A1 is associated with reduction in dolutegravir metabolism.	Details
UDP-glucuronosyltransferase 1-1	UGT1A1*37	Not Available	TA pair insertion	Effect Directly Studied	The presence of this polymorphism in UGT1A1 is associated with reduction in dolutegravir metabolism.	Details

Interactions

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This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
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Abemaciclib	Abemaciclib may decrease the excretion rate of Dolutegravir which could result in a higher serum level.
Abrocitinib	The serum concentration of Dolutegravir can be increased when it is combined with Abrocitinib.
Acamprosate	The excretion of Acamprosate can be decreased when combined with Dolutegravir.
Acyclovir	The excretion of Acyclovir can be decreased when combined with Dolutegravir.
Adagrasib	The serum concentration of Dolutegravir can be increased when it is combined with Adagrasib.

Food Interactions

Avoid multivalent ions. Cations should be separated from dolutegravir administration by 2 hours before and 6 hours after cation administration. Cations can be administered with dolutegravir if given with food.
Avoid St. John's Wort.
Take with or without food. Food, particularly high-fat meals, may increase the AUC, Cmax, and Tmax of dolutegravir.

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Dolutegravir sodium	1Q1V9V5WYQ	1051375-19-9	UGWJRRXTMKRYNK-VSLILLSYSA-M

Product Images

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Dolutegravir	Tablet, for suspension	10 mg/1	Oral	Mylan Laboratories Limited	2020-11-19	Not applicable
Tivicay	Tablet, for suspension	5 mg	Oral	Vii V Healthcare Bv	2021-03-18	Not applicable
Tivicay	Tablet, film coated	10 mg	Oral	Vii V Healthcare Bv	2020-12-16	Not applicable
Tivicay	Tablet, film coated	50 mg/1	Oral	A-S Medication Solutions	2013-08-13	2018-08-31
Tivicay	Tablet, film coated	25 mg/1	Oral	ViiV Healthcare Company	2016-06-09	Not applicable

Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End
ACRIPTEGA	Dolutegravir (50 MG) + Lamivudine (300 MG) + Tenofovir disoproxil fumarate (300 MG)	Tablet, coated	Oral	บริษัท ซาย ฟาร์มา จำกัด จำกัด	2019-12-27	Not applicable
Dovato	Dolutegravir sodium (50 mg) + Lamivudine (300 mg)	Tablet, film coated	Oral	Vii V Healthcare B.V.	2023-09-13	Not applicable
Dovato	Dolutegravir sodium (50 mg) + Lamivudine (300 mg)	Tablet	Oral	ViiV Healthcare ULC	2019-09-09	Not applicable
DOVATO	Dolutegravir (50 MG) + Lamivudine (300 MG)	Tablet, film coated	Oral	Viiv Healthcare Bv	2019-12-21	Not applicable
Dovato	Dolutegravir sodium (50 mg) + Lamivudine (300 mg)	Tablet, film coated	Oral	Vii V Healthcare B.V.	2022-06-10	Not applicable

Chemical Identifiers

UNII: DKO1W9H7M1
CAS number: 1051375-16-6
InChI Key: RHWKPHLQXYSBKR-BMIGLBTASA-N
InChI: InChI=1S/C20H19F2N3O5/c1-10-4-5-30-15-9-24-8-13(17(26)18(27)16(24)20(29)25(10)15)19(28)23-7-11-2-3-12(21)6-14(11)22/h2-3,6,8,10,15,27H,4-5,7,9H2,1H3,(H,23,28)/t10-,15+/m1/s1
IUPAC Name: (3S,7R)-N-[(2,4-difluorophenyl)methyl]-11-hydroxy-7-methyl-9,12-dioxo-4-oxa-1,8-diazatricyclo[8.4.0.0^{3,8}]tetradeca-10,13-diene-13-carboxamide
SMILES: [H][C@]12CN3C=C(C(=O)NCC4=CC=C(F)C=C4F)C(=O)C(O)=C3C(=O)N1[C@H](C)CCO2

References

General References

Min S, Song I, Borland J, Chen S, Lou Y, Fujiwara T, Piscitelli SC: Pharmacokinetics and safety of S/GSK1349572, a next-generation HIV integrase inhibitor, in healthy volunteers. Antimicrob Agents Chemother. 2010 Jan;54(1):254-8. doi: 10.1128/AAC.00842-09. Epub 2009 Nov 2. [Article]
Lenz JC, Rockstroh JK: S/GSK1349572, a new integrase inhibitor for the treatment of HIV: promises and challenges. Expert Opin Investig Drugs. 2011 Apr;20(4):537-48. doi: 10.1517/13543784.2011.562189. Epub 2011 Mar 8. [Article]
Min S, Sloan L, DeJesus E, Hawkins T, McCurdy L, Song I, Stroder R, Chen S, Underwood M, Fujiwara T, Piscitelli S, Lalezari J: Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults. AIDS. 2011 Sep 10;25(14):1737-45. doi: 10.1097/QAD.0b013e32834a1dd9. [Article]
Hare S, Smith SJ, Metifiot M, Jaxa-Chamiec A, Pommier Y, Hughes SH, Cherepanov P: Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir (S/GSK1349572). Mol Pharmacol. 2011 Oct;80(4):565-72. doi: 10.1124/mol.111.073189. Epub 2011 Jun 30. [Article]
Katlama C, Murphy R: Dolutegravir for the treatment of HIV. Expert Opin Investig Drugs. 2012 Apr;21(4):523-30. doi: 10.1517/13543784.2012.661713. Epub 2012 Mar 2. [Article]
Cahn P, Pozniak AL, Mingrone H, Shuldyakov A, Brites C, Andrade-Villanueva JF, Richmond G, Buendia CB, Fourie J, Ramgopal M, Hagins D, Felizarta F, Madruga J, Reuter T, Newman T, Small CB, Lombaard J, Grinsztejn B, Dorey D, Underwood M, Griffith S, Min S: Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet. 2013 Aug 24;382(9893):700-8. doi: 10.1016/S0140-6736(13)61221-0. Epub 2013 Jul 3. [Article]
Authors unspecified: Dolutegravir (Tivicay) for HIV. Med Lett Drugs Ther. 2013 Sep 30;55(1426):77-9. [Article]
Cottrell ML, Hadzic T, Kashuba AD: Clinical pharmacokinetic, pharmacodynamic and drug-interaction profile of the integrase inhibitor dolutegravir. Clin Pharmacokinet. 2013 Nov;52(11):981-94. doi: 10.1007/s40262-013-0093-2. [Article]
Ballantyne AD, Perry CM: Dolutegravir: first global approval. Drugs. 2013 Sep;73(14):1627-37. doi: 10.1007/s40265-013-0121-4. [Article]
Boyd MA, Donovan B: Antiretroviral therapy: dolutegravir sets SAIL(ING). Lancet. 2013 Aug 24;382(9893):664-6. doi: 10.1016/S0140-6736(13)61456-7. Epub 2013 Jul 3. [Article]
Dow DE, Bartlett JA: Dolutegravir, the Second-Generation of Integrase Strand Transfer Inhibitors (INSTIs) for the Treatment of HIV. Infect Dis Ther. 2014 Dec;3(2):83-102. doi: 10.1007/s40121-014-0029-7. Epub 2014 Jun 24. [Article]
Castellino S, Moss L, Wagner D, Borland J, Song I, Chen S, Lou Y, Min SS, Goljer I, Culp A, Piscitelli SC, Savina PM: Metabolism, excretion, and mass balance of the HIV-1 integrase inhibitor dolutegravir in humans. Antimicrob Agents Chemother. 2013 Aug;57(8):3536-46. doi: 10.1128/AAC.00292-13. Epub 2013 May 13. [Article]
Elzi L, Erb S, Furrer H, Cavassini M, Calmy A, Vernazza P, Gunthard H, Bernasconi E, Battegay M: Adverse events of raltegravir and dolutegravir. AIDS. 2017 Aug 24;31(13):1853-1858. doi: 10.1097/QAD.0000000000001590. [Article]
Adams JL, Greener BN, Kashuba AD: Pharmacology of HIV integrase inhibitors. Curr Opin HIV AIDS. 2012 Sep;7(5):390-400. doi: 10.1097/COH.0b013e328356e91c. [Article]
DeAnda F, Hightower KE, Nolte RT, Hattori K, Yoshinaga T, Kawasuji T, Underwood MR: Dolutegravir interactions with HIV-1 integrase-DNA: structural rationale for drug resistance and dissociation kinetics. PLoS One. 2013 Oct 16;8(10):e77448. doi: 10.1371/journal.pone.0077448. eCollection 2013. [Article]
ViiV Healthcare News [Link]
FDA News and Events [Link]
Johnson & Johnson News: Janssen Announces U.S. FDA Approval of First and Only Complete, Single-Pill, Two-Drug Regimen, JULUCA® (Dolutegravir and Rilpivirine), for the Treatment of HIV-1 Infection [Link]
FDA Approved Drug Products: Triumeq/Triumeq PD (abacavir, dolutegravir, and lamivudine) for oral administration [Link]
FDA Approved Drug Products: TIVICAY (dolutegravir) tablets, for oral use or oral suspension [Link]
FDA Approved Drug Products: JULUCA (dolutegravir and rilpivirine tablets), for oral use [Link]
FDA Approved Drug Products: DOVATO (dolutegravir and lamivudine) tablets, for oral use [Link]

External Links

KEGG Drug: D10066
PubChem Compound: 54726191
PubChem Substance: 175427161
ChemSpider: 25051637
BindingDB: 50062551
RxNav: 1433868
ChEBI: 76010
ChEMBL: CHEMBL1229211
ZINC: ZINC000058581064
PharmGKB: PA166114961
PDBe Ligand: DLU
Drugs.com: Drugs.com Drug Page
Wikipedia: Dolutegravir

PDB Entries

3s3m / 3s3n / 3s3o / 6rwn / 6u8q / 6vdk / 8fn7 / 8fnd / 8fng / 8fnh …

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FDA label

Download (332 KB)

MSDS

Download (61.6 KB)

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Basic Science	ART / Contraception / Human Immunodeficiency Virus (HIV) Infections	1
4	Active Not Recruiting	Treatment	Fatty Liver Disease / Human Immunodeficiency Virus (HIV) Infections	1
4	Active Not Recruiting	Treatment	Human Immunodeficiency Virus (HIV) Infections	4
4	Active Not Recruiting	Treatment	Human Immunodeficiency Virus (HIV) Infections / Human Immunodeficiency Virus Type 1 (HIV-1) Infection	1
4	Active Not Recruiting	Treatment	Human Immunodeficiency Virus (HIV) Infections / Tuberculosis (TB)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet, for suspension	Oral	10 mg/1
Tablet, film coated	Oral	52.6 MG
Tablet	Oral
Tablet	Oral	10 mg
Tablet	Oral	10.500 mg
Tablet	Oral	25 mg
Tablet	Oral	50 mg
Tablet, film coated	Oral	10 mg/1
Tablet, film coated	Oral	25 mg/1
Tablet, film coated	Oral	50 mg/1
Tablet, for suspension	Oral	5 mg
Tablet, film coated	Oral
Tablet	Oral	5.260 mg
Tablet, for suspension	Oral	5 mg/1
Tablet, film coated	Oral	50 mg
Tablet	Oral
Tablet, film coated	Oral
Tablet, coated	Oral
Kit; tablet, film coated	Oral
Tablet, film coated	Oral	10 mg
Tablet, film coated	Oral	25 mg
Tablet, coated	Oral	50 mg

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US9242986	Yes	2016-01-26	2030-06-08
US5905082	Yes	1999-05-18	2016-11-18
US6294540	Yes	2001-09-25	2018-11-14
US6417191	Yes	2002-07-09	2016-09-28
US7125879	No	2006-10-24	2022-08-09
US6838464	No	2005-01-04	2021-02-26
US8080551	No	2011-12-20	2023-04-11
US8101629	No	2012-01-24	2022-08-09
US7067522	No	2006-06-27	2019-12-20
US8129385	Yes	2012-03-06	2028-04-05
US10426780	No	2019-10-01	2031-01-24
US11234985	No	2011-01-24	2031-01-24

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	190-193ºC	MSDS
water solubility	Slightly soluble	FDA label
logP	2.2	MSDS
pKa	8.2	MSDS

Predicted Properties

Property	Value	Source
Water Solubility	0.0922 mg/mL	ALOGPS
logP	0.98	ALOGPS
logP	1.1	Chemaxon
logS	-3.7	ALOGPS
pKa (Strongest Acidic)	10.1	Chemaxon
pKa (Strongest Basic)	-0.51	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	6	Chemaxon
Hydrogen Donor Count	2	Chemaxon
Polar Surface Area	99.18 Å²	Chemaxon
Rotatable Bond Count	3	Chemaxon
Refractivity	102.77 m³·mol^-1	Chemaxon
Polarizability	40 Å³	Chemaxon
Number of Rings	4	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-00di-0030900000-4534f34038330703cccf
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0002-0091200000-6a440597a193c50eaf0b
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-004i-0090100000-0ca312dc57b4531a170b
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-016v-4298300000-ab5e8123f8bbf56aa049
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0umi-0493100000-cfb28698b53af2ff903b
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-00kp-9647100000-b74e91a03fa736ca4181
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å²)	Source type	Source
[M-H]-	203.42375	predicted	DeepCCS 1.0 (2019)
[M+H]+	205.78175	predicted	DeepCCS 1.0 (2019)
[M+Na]+	212.40889	predicted	DeepCCS 1.0 (2019)

Targets

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Details1. Integrase

Kind: Protein
Organism: Human immunodeficiency virus 1
Pharmacological action: Yes
Actions: Inhibitor

General Function: Zinc ion binding
Specific Function: Not Available
Gene Name: pol
Uniprot ID: Q7ZJM1
Uniprot Name: Integrase
Molecular Weight: 32226.645 Da

References

Hare S, Smith SJ, Metifiot M, Jaxa-Chamiec A, Pommier Y, Hughes SH, Cherepanov P: Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir (S/GSK1349572). Mol Pharmacol. 2011 Oct;80(4):565-72. doi: 10.1124/mol.111.073189. Epub 2011 Jun 30. [Article]
Waki K, Sugawara Y: Implications of integrase inhibitors for HIV-infected transplantation recipients: raltegravir and dolutegravir (S/GSK 1349572). Biosci Trends. 2011;5(5):189-91. [Article]
Underwood MR, Johns BA, Sato A, Martin JN, Deeks SG, Fujiwara T: The activity of the integrase inhibitor dolutegravir against HIV-1 variants isolated from raltegravir-treated adults. J Acquir Immune Defic Syndr. 2012 Nov 1;61(3):297-301. doi: 10.1097/QAI.0b013e31826bfd02. [Article]
Dooley KE, Sayre P, Borland J, Purdy E, Chen S, Song I, Peppercorn A, Everts S, Piscitelli S, Flexner C: Safety, tolerability, and pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: results of a phase 1 study among healthy subjects. J Acquir Immune Defic Syndr. 2013 Jan 1;62(1):21-7. doi: 10.1097/QAI.0b013e318276cda9. [Article]
Cottrell ML, Hadzic T, Kashuba AD: Clinical pharmacokinetic, pharmacodynamic and drug-interaction profile of the integrase inhibitor dolutegravir. Clin Pharmacokinet. 2013 Nov;52(11):981-94. doi: 10.1007/s40262-013-0093-2. [Article]
Rathbun RC, Lockhart SM, Miller MM, Liedtke MD: Dolutegravir, a second-generation integrase inhibitor for the treatment of HIV-1 infection. Ann Pharmacother. 2014 Mar;48(3):395-403. doi: 10.1177/1060028013513558. Epub 2013 Nov 19. [Article]

Enzymes

Details1. UDP-glucuronosyltransferase 1-1

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate

General Function: Steroid binding
Specific Function: UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name: UGT1A1
Uniprot ID: P22309
Uniprot Name: UDP-glucuronosyltransferase 1-1
Molecular Weight: 59590.91 Da

References

FDA Approved Drug Products: TIVICAY (dolutegravir) tablets, for oral use or oral suspension [Link]

Details2. Cytochrome P450 3A Subfamily (Protein Group)

Kind: Protein group
Organism: Humans
Pharmacological action: No
Actions: Substrate

General Function: Vitamin d3 25-hydroxylase activity
Specific Function: Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...

Components:

Name	UniProt ID
Cytochrome P450 3A4	P08684
Cytochrome P450 3A43	Q9HB55
Cytochrome P450 3A5	P20815
Cytochrome P450 3A7	P24462

References

FDA Approved Drug Products: TIVICAY (dolutegravir) tablets, for oral use or oral suspension [Link]

Details3. UDP-glucuronosyltransferase 1-3

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate

General Function: Retinoic acid binding
Specific Function: UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Isoform 2 lacks transferase activity but acts as a negative reg...
Gene Name: UGT1A3
Uniprot ID: P35503
Uniprot Name: UDP-glucuronosyltransferase 1-3
Molecular Weight: 60337.835 Da

References

FDA Approved Drug Products: TIVICAY (dolutegravir) tablets, for oral use or oral suspension [Link]

Details4. UDP-glucuronosyltransferase 1-9

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate

General Function: Retinoic acid binding
Specific Function: UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols. Isoform 2 lacks trans...
Gene Name: UGT1A9
Uniprot ID: O60656
Uniprot Name: UDP-glucuronosyltransferase 1-9
Molecular Weight: 59940.495 Da

References

FDA Approved Drug Products: TIVICAY (dolutegravir) tablets, for oral use or oral suspension [Link]

Carriers

Details1. Serum albumin

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Binder

General Function: Toxic substance binding
Specific Function: Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name: ALB
Uniprot ID: P02768
Uniprot Name: Serum albumin
Molecular Weight: 69365.94 Da

References

Gele T, Gouget H, Furlan V, Becker PH, Taburet AM, Lambotte O, Barrail-Tran A: Characteristics of Dolutegravir and Bictegravir Plasma Protein Binding: a First Approach for the Study of Pharmacologic Sanctuaries. Antimicrob Agents Chemother. 2020 Oct 20;64(11). pii: AAC.00895-20. doi: 10.1128/AAC.00895-20. Print 2020 Oct 20. [Article]

Details2. alpha1-acid glycoprotein (Protein Group)

Kind: Protein group
Organism: Humans
Pharmacological action: No
Actions: Binder

General Function: Not Available
Specific Function: Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...

Components:

Name	UniProt ID
Alpha-1-acid glycoprotein 1	P02763
Alpha-1-acid glycoprotein 2	P19652

References

Gele T, Gouget H, Furlan V, Becker PH, Taburet AM, Lambotte O, Barrail-Tran A: Characteristics of Dolutegravir and Bictegravir Plasma Protein Binding: a First Approach for the Study of Pharmacologic Sanctuaries. Antimicrob Agents Chemother. 2020 Oct 20;64(11). pii: AAC.00895-20. doi: 10.1128/AAC.00895-20. Print 2020 Oct 20. [Article]

Transporters

Details1. Solute carrier family 22 member 2

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Inhibitor

General Function: Quaternary ammonium group transmembrane transporter activity
Specific Function: Mediates tubular uptake of organic compounds from circulation. Mediates the influx of agmatine, dopamine, noradrenaline (norepinephrine), serotonin, choline, famotidine, ranitidine, histamin, creat...
Gene Name: SLC22A2
Uniprot ID: O15244
Uniprot Name: Solute carrier family 22 member 2
Molecular Weight: 62579.99 Da

Details2. ATP-binding cassette sub-family G member 2

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate

General Function: Xenobiotic-transporting atpase activity
Specific Function: High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name: ABCG2
Uniprot ID: Q9UNQ0
Uniprot Name: ATP-binding cassette sub-family G member 2
Molecular Weight: 72313.47 Da

Details3. Solute carrier family 22 member 6

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Inhibitor

General Function: Sodium-independent organic anion transmembrane transporter activity
Specific Function: Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one ...
Gene Name: SLC22A6
Uniprot ID: Q4U2R8
Uniprot Name: Solute carrier family 22 member 6
Molecular Weight: 61815.78 Da

Details4. Solute carrier family 22 member 8

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Inhibitor

General Function: Sodium-independent organic anion transmembrane transporter activity
Specific Function: Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenad...
Gene Name: SLC22A8
Uniprot ID: Q8TCC7
Uniprot Name: Solute carrier family 22 member 8
Molecular Weight: 59855.585 Da

Details5. P-glycoprotein 1

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate

General Function: Xenobiotic-transporting atpase activity
Specific Function: Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name: ABCB1
Uniprot ID: P08183
Uniprot Name: Multidrug resistance protein 1
Molecular Weight: 141477.255 Da

References

Adams JL, Greener BN, Kashuba AD: Pharmacology of HIV integrase inhibitors. Curr Opin HIV AIDS. 2012 Sep;7(5):390-400. doi: 10.1097/COH.0b013e328356e91c. [Article]

Details6. Multidrug and toxin extrusion protein 1

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Inhibitor

General Function: Monovalent cation:proton antiporter activity
Specific Function: Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfat...
Gene Name: SLC47A1
Uniprot ID: Q96FL8
Uniprot Name: Multidrug and toxin extrusion protein 1
Molecular Weight: 61921.585 Da

Drug created at November 11, 2013 21:17 / Updated at December 22, 2023 19:51

Dolutegravir

Identification

Structure for Dolutegravir (DB08930)

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Collision Cross Sections (CCS)

Targets

References

Enzymes

References

Components:

References

References

References

Carriers

References

Components:

References

Transporters

References