Interactions of antiretroviral drugs with the SLC22A1 (OCT1) drug transporter.

Article Details

Citation

Moss DM, Liptrott NJ, Siccardi M, Owen A

Interactions of antiretroviral drugs with the SLC22A1 (OCT1) drug transporter.

Front Pharmacol. 2015 Apr 10;6:78. doi: 10.3389/fphar.2015.00078. eCollection 2015.

PubMed ID
25914645 [ View in PubMed
]
Abstract

The SLC22A1 influx transporter is expressed on the basolateral membrane of hepatocytes and is involved in the excretion of numerous cations. Inhibition of SLC22A1 by several antiretrovirals, such as the protease inhibitor darunavir, has not previously been determined. In order to better understand and predict drug-SLC22A1 interactions, a range of antiretrovirals were screened for SLC22A1-associated inhibition and transport. Stable SLC22A1-expressing KCL22 cells were produced previously by nucleofection. Control KCL22 cells were transfected with the empty vector pcDNA3.1. Accumulation of tetraethylammonium (5.5 muM, 30 min) was determined in SLC22A1-expressing and mock-transfected cells with and without 50 muM of SLC22A1 inhibitor prazosin, or 50 muM of each antiretroviral drug. SLC22A1 IC50 values for efavirenz, darunavir, and prazosin were determined. Cellular accumulation of efavirenz and darunavir was also assessed in SLC22A1-expressing KCL22 cells and reversibility of this accumulation was assessed using prazosin. Tetraethylammonium accumulation was higher in SLC22A1-expressing cells compared to mock-transfected cells (10.6 +/- 0.8 muM vs. 0.3 +/- 0.004 muM, p = 0.009) and was significantly reduced in SLC22A1-expressing cells when co-incubated with all antiretrovirals tested except atazanavir, lamivudine, tenofovir, zidovudine, and raltegravir. Particularly noticeable was the predominance of SLC22A1 inhibitors in the protease inhibitor and non-nucleoside reverse transcriptase inhibitor classes. Absolute SLC22A1 IC50 values for efavirenz, darunavir, and prazosin were 21.8, 46.2, and 2.8 muM, respectively. Efavirenz accumulation was higher in SLC22A1-expressing cells compared to mock-transfected cells (17% higher, p = 0.009) which was reversed using prazosin, whereas no difference was observed for darunavir (p = 0.86). These data inform the mechanistic basis for disposition, drug-drug interactions and pharmacogenetic candidate gene selection for antiretroviral drugs.

DrugBank Data that Cites this Article

Drug Transporters
DrugTransporterKindOrganismPharmacological ActionActions
EfavirenzSolute carrier family 22 member 1ProteinHumans
Unknown
Inhibitor
Details
NevirapineSolute carrier family 22 member 1ProteinHumans
Unknown
Inhibitor
Details
SaquinavirSolute carrier family 22 member 1ProteinHumans
Unknown
Inhibitor
Details