Ritonavir induces P-glycoprotein expression, multidrug resistance-associated protein (MRP1) expression, and drug transporter-mediated activity in a human intestinal cell line.

Article Details

Citation

Perloff MD, Von Moltke LL, Marchand JE, Greenblatt DJ

Ritonavir induces P-glycoprotein expression, multidrug resistance-associated protein (MRP1) expression, and drug transporter-mediated activity in a human intestinal cell line.

J Pharm Sci. 2001 Nov;90(11):1829-37. doi: 10.1002/jps.1133.

PubMed ID
11745741 [ View in PubMed
]
Abstract

The present study characterized the response of P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP1) to chronic ritonavir (RIT) exposure by assessing increases in P-gp and MRP1 protein expression and activity. LS-180V intestinal carcinoma cells were exposed for 3 days to 1-100 microM RIT concurrently with controls. P-gp and MRP1 protein was quantified by Western blot analysis. Cell accumulation assays, using the P-gp substrate rhodamine 123 (RH123), the P-gp/MRP1 substrate doxorubicin (DOX), and the MRP substrate carboxyfluorescein (CBF), were performed as a measure of transporter activity. RIT strongly induced P-gp and MRP1 expression (maximum 6-fold and 3-fold increases, respectively) in a concentration-dependent fashion. Following extended exposure to RIT (> 10 microM), cells accumulated < 50% of the RH123 and DOX compared with controls, whereas accumulation of CBF was decreased by 30% at 30 microM. Differences in cell accumulation of RH123 could be eliminated with verapamil (100 microM; a P-gp inhibitor), whereas decreased DOX cell accumulation was only partially reversed by verapamil. Indomethacin (100 microM; an MRP1 inhibitor) had no significant effect on RH123 or DOX accumulation, suggesting limited MRP1-mediated activity. Thus, RIT induced protein expression of P-gp and MRP1 and increased cellular drug exclusion of RH123, DOX, and CBF. Similar in vivo phenomena may occur during anti-HIV drug therapy, explaining potential decrements in therapeutic efficacy due to decreases in bioavailability or alterations in drug distribution.

DrugBank Data that Cites this Article

Drug Transporters
DrugTransporterKindOrganismPharmacological ActionActions
RitonavirMultidrug resistance-associated protein 1ProteinHumans
Unknown
Inhibitor
Inducer
Details
RitonavirP-glycoprotein 1ProteinHumans
Unknown
Substrate
Inhibitor
Inducer
Details
Drug Interactions
DrugsInteraction
Canagliflozin
Ritonavir
The metabolism of Canagliflozin can be increased when combined with Ritonavir.
Telaprevir
Ritonavir
The serum concentration of Telaprevir can be decreased when it is combined with Ritonavir.
Interactions
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