Multidrug resistance protein 2 (MRP2) transports HIV protease inhibitors, and transport can be enhanced by other drugs

Huisman, Maarten T.; Smit, Johan W.; Crommentuyn, Kristel M. L.; Zelcer, Noam; Wiltshire, Hugh; Beijnen, Jos H.; Schinkel, Alfred H.

doi:10.1097/00002030-200211220-00009

Cited by 205 publications

(166 citation statements)

References 30 publications

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“…When present in epithelial cells, this protein is found primarily in the basolateral membrane (Hipfner et al, 1999). However, it has been reported that MRP1 does not mediate substantial polarized transport of PIs in MDCKII-MRP1 cells (Huisman et al, 2002). In contrast to MRP1, MRP2 is localized on the apical membrane of several epithelia.…”

Section: Introductionmentioning

confidence: 97%

“…Functionally it is similar to P-gp mediated elimination of toxic compounds in gut and placenta (Kruh and Belinsky, 2003). It has been fairly established that MRP2 effluxes PIs (Huisman et al, 2002;Williams et al, 2002).…”

Section: Introductionmentioning

confidence: 98%

“…P-gp is present on the apical membrane of many absorptive epithelial and endothelial cells. Because of its localization and distribution, P-gp limits the oral absorption and bioavailability of PIs across intestine, brain, testis and placenta (Kim et al, 1998;Polli et al, 1999;Smit et al, 1999;Choo et al, 2000;Huisman et al, 2001;Huisman et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies have demonstrated that the PIs are also substrates for the MRPs, belonging to the same ABC transporter family (Huisman et al, 2002;Bachmeier et al, 2005). So far, eight MRP homologs have been identified for ABC proteins, MRP1-8.…”

Section: Introductionmentioning

confidence: 99%

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Both P-gp and MRP2 mediate transport of Lopinavir, a protease inhibitor

Agarwal

Pal

Mitra

2007

International Journal of Pharmaceutics

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Polarized epithelial non-human (canine) cell lines stably transfected with human or murine complementary DNA (cDNA) encoding for various efflux transporters (P-gp/MDR1, MRP1, MRP2, and Bcrp1) were used to study transepithelial transport of Lopinavir (LVR) and compare results with the MDCKII-Wild type cells. These transmembrane proteins cause multidrug resistance by decreasing the total intracellular accumulation of drugs. Lopinavir efflux was directional and was completely inhibited by MK-571, a selective MRP family inhibitor in the MDCKII-MRP2 cell line. Similarly, LVR efflux was also inhibited by P-gp inhibitors P-gp 4008 and GF120918 in the MDCKII-MDR1 cell line. The efflux ratios (Efflux rate/ Influx rate) of LVR in the absence of any efflux inhibitors in the MDCK-Wild type, MDCKII-MDR1, MDCKII-MRP1 and MDCKII-MRP2 cell monolayers were 1.32, 4.91, 1.26 and 2.89 respectively. The MDCKII-MDR1 and MDCKII-MRP2 cells have significantly increased LVR efflux ratio relative to the parental cells due to the apically directed transport by MDR1 and MRP2 respectively. The efflux ratios in MRP2 and MDR1 transfected cell lines were close to unity in the presence of MK-571 and P-gp 4008 respectively; indicating that LVR efflux by MRP2 and P-gp was completely inhibited by their selective inhibitors. MDCKII-MRP1 cells did not exhibit a significant reduction in the LVR efflux relative to the parental cells, indicating that LVR is not a good substrate for MRP1. Transport studies across MDCKII-Bcrp1 cells indicated that LVR is not transported by Bcrp1 and is not a substrate for this efflux protein. In conclusion, this study presents direct evidence that LVR is effluxed by both P-gp and MRP2 which may contribute to its poor oral bioavailability and limited penetration into the CNS. KeywordsMDCKII-MDR1; MDCKII-MRP2; MDCKII-MRP1; MDCKII-Bcrp1; MDCKII-WT; Pglycoprotein (P-gp); multidrug resistance protein (MRP); breast cancer resistance protein (BCRP); Lopinavir (LVR); uptake; transport; permeability; efflux ratio (ER)

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Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Both P-gp and MRP2 mediate transport of Lopinavir, a protease inhibitor

Agarwal

Pal

Mitra

2007

International Journal of Pharmaceutics

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“…In the liver, Mrp2 is a canalicular transporter involved in the biliary excretion of many endogenous and exogenous metabolites, including leukotrienes and bilirubin, and many drugs, such as protease inhibitors. [1][2][3] Mrp3 and Mrp4 are high-capacity, low-affinity basolateral transporters that are highly inducible. These hepatoprotective transporters export conjugated bile acids, bilirubin, and other substrates from hepatocytes back into the bloodstream for renal excretion.…”

mentioning

confidence: 99%

Oxidative and electrophilic stress induces multidrug resistance-associated protein transporters via the nuclear factor-E2-related factor-2 transcriptional pathway

et al. 2007

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Multidrug resistance-associated proteins (Mrps) are adenosine triphosphate-dependent transporters that efflux chemicals out of cells. In the liver, Mrp2 transports bilirubinglucuronide, glutathione (GSH), and drug conjugates into bile, whereas Mrp3 and Mrp4 efflux these entities into blood. The purpose of this study was to determine whether oxidative conditions (that is, the disruption of hepatic GSH synthesis) or the administration of nuclear factor-E2-related factor-2 (Nrf2)

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