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 μmol/L), BCRP (IC(50) = 1.5 ± 0.3 μmol/L), OATP1B1 (IC(50) = 4.1 ± 1.8 μmol/L), OATP1B3 (IC(50) = 6.1 ± 0.9 μmol/L),
CYP3A4 (IC(50) = 1.3 ± 0.6 μmol/L),
CYP2C19 (IC(50) = 2.7 ± 0.3 μmol/L) and
CYP2B6 (IC(50) = 4.2 ± 1.6 μmol/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.