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In vitro investigations into the roles of drug transporters and metabolizing enzymes in the disposition and drug interactions of dolutegravir, a HIV integrase inhibitor.
Drug Metab Dispos. 2013 Feb; 41(2):353-61.DM

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.

Authors+Show Affiliations

Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. mindy.j.reese@gsk.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23132334

Citation

Reese, Melinda J., et al. "In Vitro Investigations Into the Roles of Drug Transporters and Metabolizing Enzymes in the Disposition and Drug Interactions of Dolutegravir, a HIV Integrase Inhibitor." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 41, no. 2, 2013, pp. 353-61.
Reese MJ, Savina PM, Generaux GT, et al. In vitro investigations into the roles of drug transporters and metabolizing enzymes in the disposition and drug interactions of dolutegravir, a HIV integrase inhibitor. Drug Metab Dispos. 2013;41(2):353-61.
Reese, M. J., Savina, P. M., Generaux, G. T., Tracey, H., Humphreys, J. E., Kanaoka, E., Webster, L. O., Harmon, K. A., Clarke, J. D., & Polli, J. W. (2013). In vitro investigations into the roles of drug transporters and metabolizing enzymes in the disposition and drug interactions of dolutegravir, a HIV integrase inhibitor. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 41(2), 353-61. https://doi.org/10.1124/dmd.112.048918
Reese MJ, et al. In Vitro Investigations Into the Roles of Drug Transporters and Metabolizing Enzymes in the Disposition and Drug Interactions of Dolutegravir, a HIV Integrase Inhibitor. Drug Metab Dispos. 2013;41(2):353-61. PubMed PMID: 23132334.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vitro investigations into the roles of drug transporters and metabolizing enzymes in the disposition and drug interactions of dolutegravir, a HIV integrase inhibitor. AU - Reese,Melinda J, AU - Savina,Paul M, AU - Generaux,Grant T, AU - Tracey,Helen, AU - Humphreys,Joan E, AU - Kanaoka,Eri, AU - Webster,Lindsey O, AU - Harmon,Kelly A, AU - Clarke,James D, AU - Polli,Joseph W, Y1 - 2012/11/06/ PY - 2012/11/8/entrez PY - 2012/11/8/pubmed PY - 2013/7/16/medline SP - 353 EP - 61 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 41 IS - 2 N2 - 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. SN - 1521-009X UR - https://www.unboundmedicine.com/medline/citation/23132334/In_vitro_investigations_into_the_roles_of_drug_transporters_and_metabolizing_enzymes_in_the_disposition_and_drug_interactions_of_dolutegravir_a_HIV_integrase_inhibitor_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=23132334 DB - PRIME DP - Unbound Medicine ER -