title: Raltegravir has a low propensity to cause clinical drug interactions through inhibition of major drug transporters: an in vitro evaluation.
abstract: Raltegravir (RAL) is a human immunodeficiency virus type 1 (HIV-1) integrase inhibitor approved to treat HIV infection in adults in combination with other antiretrovirals. The potential of RAL to cause transporter-related drug-drug interactions (DDIs) as an inhibitor has not been well described to date. In this study, a series of in vitro experiments were conducted to assess the inhibitory effects of RAL on major human drug transporters known to be involved in clinically relevant drug interactions, including hepatic and renal uptake transporters and efflux transporters. For hepatic uptake transporters, RAL showed no inhibition of organic anion-transporting polypeptide 1B1 (OATP1B1), weak inhibition of OATP1B3 (40% inhibition at 100 μM), and no inhibition of organic cation transporter 1 (OCT1). Studies of renal uptake transporters showed that RAL inhibited organic anion transporters 1 and 3 (OAT1 and OAT3) with 50% inhibitory concentrations (IC50s) (108 μM and 18.8 μM, respectively) well above the maximum concentration of drug in plasma (Cmax) at the clinical 400-mg dose and did not inhibit organic cation transporter 2 (OCT2). As for efflux transporters, RAL did not inhibit breast cancer resistance protein (BCRP) and showed weak inhibition of multidrug and toxin extrusion protein 1 (MATE1) (52% inhibition at 100 μM) and MATE2-K (29% inhibition at 100 μM). These studies indicate that at clinically relevant exposures, RAL does not inhibit or only weakly inhibits hepatic uptake transporters OATP1B1, OATP1B3, and OCT1, renal uptake transporters OCT2, OAT1, and OAT3, as well as efflux transporters BCRP, MATE1, and MATE2-K. The propensity for RAL to cause DDIs via inhibition of these transporters is therefore considered low.
authors.affiliation: Merck & Co., Inc., Whitehouse Station, New Jersey, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Rizk
authors.forename: Robert
authors.initials: R
authors.lastname: Houle
authors.forename: Grace Hoyee
authors.initials: GH
authors.lastname: Chan
authors.forename: Mike
authors.initials: M
authors.lastname: Hafey
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Rhee
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Chu
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects; D000818:Animals; D004285:Dogs; D004347:Drug Interactions; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D027381:Liver-Specific Organic Anion Transporter 1; D061985:Madin Darby Canine Kidney Cells; D026901:Membrane Transport Proteins / Q000187:drug effects*; D009363:Neoplasm Proteins / Q000187:drug effects; D027362:Organic Anion Transport Protein 1 / Q000187:drug effects; D027361:Organic Anion Transporters / Q000187:drug effects; D029362:Organic Anion Transporters, Sodium-Independent / Q000187:drug effects; D027701:Organic Cation Transport Proteins / Q000187:drug effects; D027702:Organic Cation Transporter 1 / Q000187:drug effects; D000075102:Organic Cation Transporter 2; D011760:Pyrrolidinones / Q000494:pharmacology*; D000068898:Raltegravir Potassium; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D019428:HIV Integrase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D026901:Membrane Transport Proteins; D009363:Neoplasm Proteins; D027362:Organic Anion Transport Protein 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D000075102:Organic Cation Transporter 2; D011760:Pyrrolidinones; C491013:SLC22A2 protein, human; C521869:SLC47A1 protein, human; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; C114338:organic anion transport protein 3; D000068898:Raltegravir Potassium