Document Detail

Raltegravir is a substrate for SLC22A6: a putative mechanism for the interaction between raltegravir and tenofovir.
MedLine Citation:
PMID:  21078936     Owner:  NLM     Status:  MEDLINE    
The identification of transporters of the HIV integrase inhibitor raltegravir could be a factor in an understanding of the pharmacokinetic-pharmacodynamic relationship and reported drug interactions of raltegravir. Here we determined whether raltegravir was a substrate for ABCB1 or the influx transporters SLCO1A2, SLCO1B1, SLCO1B3, SLC22A1, SLC22A6, SLC10A1, SLC15A1, and SLC15A2. Raltegravir transport by ABCB1 was studied with CEM, CEM(VBL100), and Caco-2 cells. Transport by uptake transporters was assessed by using a Xenopus laevis oocyte expression system, peripheral blood mononuclear cells, and primary renal cells. The kinetics of raltegravir transport and competition between raltegravir and tenofovir were also investigated using SLC22A6-expressing oocytes. Raltegravir was confirmed to be an ABCB1 substrate in CEM, CEM(VBL100), and Caco-2 cells. Raltegravir was also transported by SLC22A6 and SLC15A1 in oocyte expression systems but not by other transporters studied. The K(m) and V(max) for SLC22A6 transport were 150 μM and 36 pmol/oocyte/h, respectively. Tenofovir and raltegravir competed for SLC22A6 transport in a concentration-dependent manner. Raltegravir inhibited 1 μM tenofovir with a 50% inhibitory concentration (IC(50)) of 14.0 μM, and tenofovir inhibited 1 μM raltegravir with an IC(50) of 27.3 μM. Raltegravir concentrations were not altered by transporter inhibitors in peripheral blood mononuclear cells or primary renal cells. Raltegravir is a substrate for SLC22A6 and SLC15A1 in the oocyte expression system. However, transport was limited compared to endogenous controls, and these transporters are unlikely to have a great impact on raltegravir pharmacokinetics.
Darren M Moss; Wai San Kwan; Neill J Liptrott; Darren L Smith; Marco Siccardi; Saye H Khoo; David J Back; Andrew Owen
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-11-15
Journal Detail:
Title:  Antimicrobial agents and chemotherapy     Volume:  55     ISSN:  1098-6596     ISO Abbreviation:  Antimicrob. Agents Chemother.     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2011-01-21     Completed Date:  2011-05-19     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  0315061     Medline TA:  Antimicrob Agents Chemother     Country:  United States    
Other Details:
Languages:  eng     Pagination:  879-87     Citation Subset:  IM    
Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom.
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MeSH Terms
Adenine / analogs & derivatives*,  metabolism
Anti-HIV Agents / metabolism*
Biological Transport
Caco-2 Cells
Cell Line
Drug Interactions
HIV Integrase Inhibitors / metabolism*
Kidney / cytology,  metabolism
Leukocytes, Mononuclear / metabolism
Oocytes / metabolism
Organic Anion Transport Protein 1 / metabolism*
Organophosphonates / metabolism*
Pyrrolidinones / metabolism*
Reverse Transcriptase Inhibitors / metabolism*
Substrate Specificity
Xenopus laevis / metabolism
Reg. No./Substance:
0/Anti-HIV Agents; 0/HIV Integrase Inhibitors; 0/Organic Anion Transport Protein 1; 0/Organophosphonates; 0/Pyrrolidinones; 0/Reverse Transcriptase Inhibitors; 107021-12-5/tenofovir; 22VKV8053U/raltegravir; 73-24-5/Adenine

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