Potential of the novel antiretroviral drug rilpivirine to modulate the expression and function of drug transporters and drug-metabolising enzymes in vitro.

Article Details

Citation

Weiss J, Haefeli WE

Potential of the novel antiretroviral drug rilpivirine to modulate the expression and function of drug transporters and drug-metabolising enzymes in vitro.

Int J Antimicrob Agents. 2013 May;41(5):484-7. doi: 10.1016/j.ijantimicag.2013.01.004. Epub 2013 Feb 18.

PubMed ID
23428312 [ View in PubMed
]
Abstract

The objective of this study was to assess the drug-drug interaction potential of the new non-nucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine in vitro. The following were evaluated: P-glycoprotein (P-gp/ABCB1) inhibition by calcein assay; breast cancer resistance protein (BCRP/ABCG2) inhibition by pheophorbide A efflux; and inhibition of organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 by 8-fluorescein-cAMP uptake. Inhibition of cytochrome P450 enzymes was assessed using commercially available kits. Substrate characteristics were evaluated by growth inhibition assays in MDCKII cells overexpressing particular ABC transporters. Induction of drug-metabolising enzymes and transporters was quantified by real-time RT-PCR in LS180 cells, and activation of pregnane X receptor (PXR) by a reporter gene assay. Rilpivirine significantly inhibited P-gp (IC(50) = 13.1 +/- 6.8 mumol/L), BCRP (IC(50) = 1.5 +/- 0.3 mumol/L), OATP1B1 (IC(50) = 4.1 +/- 1.8 mumol/L), OATP1B3 (IC(50) = 6.1 +/- 0.9 mumol/L), CYP3A4 (IC(50) = 1.3 +/- 0.6 mumol/L), CYP2C19 (IC(50) = 2.7 +/- 0.3 mumol/L) and CYP2B6 (IC(50) = 4.2 +/- 1.6 mumol/L). Growth inhibition assays indicate that rilpivirine is not a substrate of P-gp, BCRP, or multidrug resistance-associated proteins 1 and 2. In LS180 cells, rilpivirine induced mRNA expression of ABCB1, CYP3A4 and UGT1A3, whereas ABCC1, ABCC2, ABCG2, OATP1B1 and UGT1A9 were not induced. Moreover, rilpivirine was a PXR activator. In conclusion, rilpivirine inhibits and induces several relevant drug-metabolising enzymes and drug transporters, but owing to its low plasma concentrations it is most likely less prone to drug-drug interactions than older NNRTIs.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
RilpivirineCytochrome P450 2B6ProteinHumans
Unknown
Inhibitor
Details
RilpivirineCytochrome P450 2C19ProteinHumans
Unknown
Substrate
Inhibitor
Details
RilpivirineCytochrome P450 2D6ProteinHumans
Unknown
Inhibitor
Details
RilpivirineCytochrome P450 3A4ProteinHumans
No
Substrate
Inhibitor
Inducer
Details
Drug Transporters
DrugTransporterKindOrganismPharmacological ActionActions
RilpivirineATP-binding cassette sub-family G member 2ProteinHumans
Unknown
Inhibitor
Details
RilpivirineP-glycoprotein 1ProteinHumans
Unknown
Inhibitor
Details
RilpivirineSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Inhibitor
Details
RilpivirineSolute carrier organic anion transporter family member 1B3ProteinHumans
Unknown
Inhibitor
Details