Abstract
Dolutegravir (DTG; S/GSK1349572) is a potent HIV-1 integrase inhibitor with a distinct resistance profile and a once-daily dose regimen that does not require pharmacokinetic boosting. This work investigated the in vitro drug transport and metabolism of DTG and assessed the potential for clinical drug-drug interactions. DTG is a substrate for the efflux transporters P-glycoprotein (Pgp) and human breast cancer resistance protein (BCRP). Its high intrinsic membrane permeability limits the impact these transporters have on DTG's intestinal absorption. UDP-glucuronosyltransferase (UGT) 1A1 is the main enzyme responsible for the metabolism of DTG in vivo, with cytochrome P450 (P450) 3A4 being a notable pathway and UGT1A3 and UGT1A9 being only minor pathways. DTG demonstrated little or no inhibition (IC(50) values > 30 μM) in vitro of the transporters Pgp, BCRP, multidrug resistance protein 2, organic anion transporting polypeptide 1B1/3, organic cation transporter (OCT) 1, or the drug metabolizing enzymes CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, UGT1A1, or 2B7. Further, DTG did not induce CYP1A2, 2B6, or 3A4 mRNA in vitro using human hepatocytes. DTG does inhibit the renal OCT2 (IC(50) = 1.9 μM) transporter, which provides a mechanistic basis for the mild increases in serum creatinine observed in clinical studies. These in vitro studies demonstrate a low propensity for DTG to be a perpetrator of clinical drug interactions and provide a basis for predicting when other drugs could result in a drug interaction with DTG.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters / antagonists & inhibitors
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ATP-Binding Cassette Transporters / metabolism
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Animals
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CHO Cells
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Cricetinae
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Cricetulus
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Cytochrome P-450 Enzyme Inhibitors
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Cytochrome P-450 Enzyme System / genetics
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Cytochrome P-450 Enzyme System / metabolism*
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Dogs
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Drug Interactions
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Enzyme Induction
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Female
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Glucuronosyltransferase / antagonists & inhibitors
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Glucuronosyltransferase / genetics
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Glucuronosyltransferase / metabolism*
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HIV Integrase Inhibitors / metabolism*
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HIV Integrase Inhibitors / pharmacology
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Hepatocytes / drug effects
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Hepatocytes / enzymology*
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Heterocyclic Compounds, 3-Ring / metabolism*
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Heterocyclic Compounds, 3-Ring / pharmacology
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Humans
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Isoenzymes
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Madin Darby Canine Kidney Cells
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Male
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Membrane Transport Proteins / drug effects
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Membrane Transport Proteins / genetics
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Membrane Transport Proteins / metabolism*
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Microsomes, Liver / drug effects
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Microsomes, Liver / enzymology*
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Multidrug Resistance-Associated Protein 2
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Multidrug Resistance-Associated Proteins / antagonists & inhibitors
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Multidrug Resistance-Associated Proteins / metabolism
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / metabolism
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Organic Anion Transporters / antagonists & inhibitors
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Organic Anion Transporters / metabolism
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Oxazines
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Piperazines
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Pyridones
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Transfection
Substances
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ABCB1 protein, human
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ABCG2 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters
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Cytochrome P-450 Enzyme Inhibitors
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HIV Integrase Inhibitors
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Heterocyclic Compounds, 3-Ring
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Isoenzymes
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Membrane Transport Proteins
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Multidrug Resistance-Associated Protein 2
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Multidrug Resistance-Associated Proteins
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Neoplasm Proteins
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Organic Anion Transporters
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Oxazines
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Piperazines
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Pyridones
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Cytochrome P-450 Enzyme System
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dolutegravir
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Glucuronosyltransferase