Interaction of HIV protease inhibitors with OATP1B1, 1B3, and 2B1.

Article Details

Citation

Annaert P, Ye ZW, Stieger B, Augustijns P

Interaction of HIV protease inhibitors with OATP1B1, 1B3, and 2B1.

Xenobiotica. 2010 Mar;40(3):163-76. doi: 10.3109/00498250903509375.

PubMed ID
20102298 [ View in PubMed
]
Abstract

The effects of human immunodeficiency virus (HIV) protease inhibitors (PI) on the accumulation of the fluorescent bile salt analogue cholyl-glycylamido-fluorescein (CGamF) were determined in organic anion transporting polypeptide (OATP)-1B1 and -1B3-expressing Chinese hamster ovary (CHO) cells. In addition, interaction studies in Caco-2 monolayers, known only to express the OATP2B1 isoform, were conducted using the established OATP substrate estrone 3-sulfate (E3S), since no CGamF accumulation was observed in Caco-2 monolayers. CGamF appeared an excellent substrate for the OATP1B subfamily, with net accumulation clearance values of 7.8 and 142 microl min(-1) mg(-1) protein in OATP1B1 and OATP1B3-transfected cells, respectively. K(i)-values reflecting inhibition of CGamF accumulation by HIV PI correlated well between OATP1B1 and OATP1B3-expressing cells. Lopinavir was the most potent inhibitor (K(i) = 0.5-1.4 microM) of OATP1B-mediated CGamF accumulation compared with atazanavir, darunavir, ritonavir, and saquinavir (K(i) between 1.4 and 3.3 microM). Inhibitory profiles towards OATP2B1-mediated E3S accumulation were different with only indinavir, saquinavir, and ritonavir showing substantial effects. In conclusion, OATP1B3 appears to be a major transport mechanism mediating sodium-independent CGamF accumulation in human liver, and CGamF could be used as a probe substrate for in vitro drug interaction studies. The remarkably potent inhibition of OATP1B1 by lopinavir may explain some clinically relevant drug interactions between lopinavir and OATP1B substrates such as fexofenadine.

DrugBank Data that Cites this Article

Drug Transporters
DrugTransporterKindOrganismPharmacological ActionActions
AtazanavirSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
DarunavirSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
IndinavirSolute carrier organic anion transporter family member 2B1ProteinHumans
Unknown
Inhibitor
Details
LopinavirSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
LopinavirSolute carrier organic anion transporter family member 1B3ProteinHumans
Unknown
Inhibitor
Details
RitonavirSolute carrier organic anion transporter family member 2B1ProteinHumans
Unknown
Inhibitor
Details
SaquinavirSolute carrier organic anion transporter family member 2B1ProteinHumans
Unknown
Inhibitor
Details
Drug Interactions
DrugsInteraction
Darunavir
Bosentan
The serum concentration of Darunavir can be decreased when it is combined with Bosentan.
Eluxadoline
Valsartan
The serum concentration of Eluxadoline can be increased when it is combined with Valsartan.
Eluxadoline
Troglitazone
The serum concentration of Eluxadoline can be increased when it is combined with Troglitazone.
Eluxadoline
Erythromycin
The serum concentration of Eluxadoline can be increased when it is combined with Erythromycin.
Eluxadoline
Sildenafil
The serum concentration of Eluxadoline can be increased when it is combined with Sildenafil.
Eluxadoline
Reserpine
The serum concentration of Eluxadoline can be increased when it is combined with Reserpine.
Eluxadoline
Pantoprazole
The serum concentration of Eluxadoline can be increased when it is combined with Pantoprazole.
Eluxadoline
Nelfinavir
The serum concentration of Eluxadoline can be increased when it is combined with Nelfinavir.
Eluxadoline
Indinavir
The serum concentration of Eluxadoline can be increased when it is combined with Indinavir.
Eluxadoline
Lovastatin
The serum concentration of Eluxadoline can be increased when it is combined with Lovastatin.
Interactions
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