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Raltegravir has a low propensity to cause clinical drug interactions through inhibition of major drug transporters: an in vitro evaluation.
Antimicrob Agents Chemother. 2014; 58(3):1294-301.AA

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+Show Affiliations

Merck & Co., Inc., Whitehouse Station, New Jersey, USA.No 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

24295974

Citation

Rizk, Matthew L., et al. "Raltegravir Has a Low Propensity to Cause Clinical Drug Interactions Through Inhibition of Major Drug Transporters: an in Vitro Evaluation." Antimicrobial Agents and Chemotherapy, vol. 58, no. 3, 2014, pp. 1294-301.
Rizk ML, Houle R, Chan GH, et al. Raltegravir has a low propensity to cause clinical drug interactions through inhibition of major drug transporters: an in vitro evaluation. Antimicrob Agents Chemother. 2014;58(3):1294-301.
Rizk, M. L., Houle, R., Chan, G. H., Hafey, M., Rhee, E. G., & Chu, X. (2014). Raltegravir has a low propensity to cause clinical drug interactions through inhibition of major drug transporters: an in vitro evaluation. Antimicrobial Agents and Chemotherapy, 58(3), 1294-301. https://doi.org/10.1128/AAC.02049-13
Rizk ML, et al. Raltegravir Has a Low Propensity to Cause Clinical Drug Interactions Through Inhibition of Major Drug Transporters: an in Vitro Evaluation. Antimicrob Agents Chemother. 2014;58(3):1294-301. PubMed PMID: 24295974.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Raltegravir has a low propensity to cause clinical drug interactions through inhibition of major drug transporters: an in vitro evaluation. AU - Rizk,Matthew L, AU - Houle,Robert, AU - Chan,Grace Hoyee, AU - Hafey,Mike, AU - Rhee,Elizabeth G, AU - Chu,Xiaoyan, Y1 - 2013/12/02/ PY - 2013/12/4/entrez PY - 2013/12/4/pubmed PY - 2014/10/29/medline SP - 1294 EP - 301 JF - Antimicrobial agents and chemotherapy JO - Antimicrob. Agents Chemother. VL - 58 IS - 3 N2 - 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. SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/24295974/Raltegravir_has_a_low_propensity_to_cause_clinical_drug_interactions_through_inhibition_of_major_drug_transporters:_an_in_vitro_evaluation_ L2 - http://aac.asm.org/cgi/pmidlookup?view=long&pmid=24295974 DB - PRIME DP - Unbound Medicine ER -