Intestinal Transport of Irinotecan in Caco-2 Cells and MDCK II Cells Overexpressing Efflux Transporters Pgp, cMOAT, and MRP1

Luo, Feng; Paranjpe, Pankaj V.; Guo, Ailan; Rubin, Eric H.; Sinko, Patrick J.

doi:10.1124/dmd.30.7.763

Cited by 106 publications

(46 citation statements)

References 25 publications

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“…This is in accord with previous reports showing similar results with topotecan (de Vries et al, 2007;Sharom, 2008). Other camptothecin analogs have also been shown to be substrates of BCRP, which was reported to transport irinotecan, SN-38, and SN-38 glucuronide (Maliepaard et al, 1999;Nakatomi et al, 2001;Luo et al, 2002). Our studies also showed that AR-67 carboxylate is transported by OATP1B1 and OATP1B3 (Fig.…”

Section: Discussionsupporting

confidence: 83%

“…Topotecan and the active irinotecan metabolite SN-38 (7-ethyl-10-hydroxy-camptothecin) have been identified as breast cancer resistance protein (BCRP) substrates de Vries et al, 2007) whereas transport mediated by multidrug resistant protein 1 (MDR1) has been reported for topotecan and irinotecan (Luo et al, 2002;de Vries et al, 2007). Notably, expression of BCRP in established cancer cell lines and tumor biopsy samples has been associated with resistance to camptothecins Candeil et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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The Effect of Breast Cancer Resistance Protein, Multidrug Resistant Protein 1, and Organic Anion-Transporting Polypeptide 1B3 on the Antitumor Efficacy of the Lipophilic Camptothecin 7-t-Butyldimethylsilyl-10-Hydroxycamptothecin (AR-67) In Vitro

et al. 2013

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AR-67 (7-t-butyldimethylsilyl-10-hydroxycamptothecin) is a lipophilic camptothecin analog, currently under early stage clinical trials. Transporters are known to have an impact on the disposition of camptothecins and on the response to chemotherapeutics in general due to their expression in tumor tissues. Therefore, we investigated the interplay between the breast cancer resistance protein (BCRP), multidrug resistant protein 1 (MDR1), and organic anion-transporting polypeptide (OATP) 1B1/1B3 transporters and AR-67 and their impact on the toxicity profile of AR-67. Using cell lines expressing the aforementioned transporters, we showed that the lipophilic AR-67 lactone form is a substrate for efflux transporters BCRP and MDR1. Additionally, OATP1B1 and OATP1B3 facilitated the uptake of AR-67 carboxylate in SLCO1B1-and SLCO1B3-transfected cell systems compared with the mocktransfected ones. Notably, both BCRP and MDR1 conferred resistance to AR-67 lactone. Prompted by recent studies showing increased OATP1B3 expression in certain cancer types, we investigated the effect of OATP1B3 expression on cell viability after exposure to AR-67 carboxylate. OATP1B3-expressing cells had increased carboxylate uptake as compared with mock-transfected cells but were not sensitized because the intracellular amount of lactone was 50-fold higher than that of carboxylate and comparable between OATP1B3-expressing and OATP1B3-nonexpressing cells.In conclusion, BCRP-and MDR1-mediated efflux of AR-67 lactone confers resistance to AR-67, but OATP1B3-mediated uptake of the AR-67 carboxylate does not sensitize OATP1B3-expressing tumor cells.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

The Effect of Breast Cancer Resistance Protein, Multidrug Resistant Protein 1, and Organic Anion-Transporting Polypeptide 1B3 on the Antitumor Efficacy of the Lipophilic Camptothecin 7-t-Butyldimethylsilyl-10-Hydroxycamptothecin (AR-67) In Vitro

et al. 2013

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“…(11) Efflux of the parent compound and metabolites out of cells by several other transporters (e.g., ABCG2, ABCC1) also occurs. (12,13) Liver uptake transporters might also be involved in the disposition of irinotecan and its metabolites. (14) Investigators have uncovered some genetic sources of variation in the drug's pharmacokinetics.…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetic Pathway Analysis of Irinotecan

Rosner

Panetta

Innocenti

et al. 2008

Clin Pharmacol Ther

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Irinotecan, a chemotherapeutic agent for various solid tumors, is a prodrug requiring activation to SN-38. Irinotecan's complex pharmacokinetics allows for potentially many genetic sources of variability. We explored relationships between pharmacokinetic pathways and polymorphisms in genes associated with irinotecan's metabolism and transport. We fit a seven-compartment pharmacokinetic model with enterohepatic recirculation to concentrations of irinotecan and metabolites SN-38, SN-38G (glucuronide), and APC. Principal component analysis (PCA) of patientspecific parameter estimates produced measures interpretable along pathways. Nine principal components characterized overall variation well. Polymorphisms in genes UGT1A1, UGT1A7, and UGT1A9 had strong associations with a component corresponding to the irinotecan-to-SN-38 pathway and SN-38 recirculation and to a component relating to SN-38-to-SN-38G conversion and SN-38G's elimination. The component characterizing irinotecan's compartments was associated with HNF1α and ABCC2 polymorphisms. The exploratory analysis with PCA in this pharmacogenetic analysis identified known associations and may have allowed identification of previously uncharacterized functional polymorphisms.

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“…MRP2 is expressed in many solid human tumors originating from kidney, colon, breast, lung, and ovary (Sandusky et al, 2002), and it was shown that the protein actively transports many types of anticancer and other drugs like vinca alkaloids, anthracyclines, protease inhibitors, antibiotics, etoposide, cisplatin, methotrexate, and irinotecan in vitro (Bakos et al, 2000;Borst and Oude Elferink, 2002;Luo et al, 2002;Chan et al, 2004). Mrp2 is involved in vivo in the excretion of methotrexate and irinotecan and its metabolites into the bile, as was demonstrated in Mrp2-deficient rats (Chu et al, 1997;Masuda et al, 1997).…”

mentioning

confidence: 99%

Carcinogen and Anticancer Drug Transport by Mrp2 in Vivo: Studies UsingMrp2(Abcc2) Knockout Mice

Vlaming¹,

Mohrmann²,

Wagenaar³

et al. 2006

J Pharmacol Exp Ther

142

159

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The ATP-binding-cassette (ABC) transporter multidrug resistance protein (MRP) 2 (ABCC2) forms a natural barrier and efflux system for various (conjugates of) drugs, other xenotoxins, and endogenous compounds. To obtain insight in the pharmacological and physiological functions of Mrp2, we generated Mrp2 knockout mice, which were viable and fertile but suffered from mild hyperbilirubinemia due to impaired excretion of bilirubin monoglucuronides into bile. The mice also had an 80-fold decreased biliary glutathione excretion and a 63% reduced bile flow. Levels of Mrp3 (Abcc3) in liver and Mrp4 The multidrug transporter MRP2 (ABCC2, cMOAT), a member of the ATP-binding-cassette (ABC) superfamily, confers resistance to a range of anticancer drugs (Borst and Oude Elferink, 2002;Chan et al., 2004). The protein is mainly present in the apical membranes of polarized cells in liver, small intestine, and kidney and mediates active transport of both endogenous and xenobiotic compounds to bile, urine, or feces (Chan et al., 2004). MRP2 is functionally deficient in patients with the Dubin-Johnson syndrome (Zimniak, 1993), in TR Ϫ rats (Jansen et al., 1985), and Eisai hyperbilirubinemic rats (EHBRs) (Hosokawa et al., 1992), which all show impaired secretion of bilirubin glucuronides into the bile and as a consequence suffer from conjugated hyperbilirubinemia (Jansen et al., 1985; Hosokawa et al., 1992;Zimniak, 1993). The mutant rat strains also show substantially reduced biliary excretion of glutathione and glutathione conjugates (Paulusma et al., 1999).Besides its role in transport of endogenous compounds, MRP2 plays an important role in the transport of various 1 These authors contributed equally to this work. Article, publication date, and citation information can be found at

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Intestinal Transport of Irinotecan in Caco-2 Cells and MDCK II Cells Overexpressing Efflux Transporters Pgp, cMOAT, and MRP1

Cited by 106 publications

References 25 publications

The Effect of Breast Cancer Resistance Protein, Multidrug Resistant Protein 1, and Organic Anion-Transporting Polypeptide 1B3 on the Antitumor Efficacy of the Lipophilic Camptothecin 7-t-Butyldimethylsilyl-10-Hydroxycamptothecin (AR-67) In Vitro

The Effect of Breast Cancer Resistance Protein, Multidrug Resistant Protein 1, and Organic Anion-Transporting Polypeptide 1B3 on the Antitumor Efficacy of the Lipophilic Camptothecin 7-t-Butyldimethylsilyl-10-Hydroxycamptothecin (AR-67) In Vitro

Pharmacogenetic Pathway Analysis of Irinotecan

Carcinogen and Anticancer Drug Transport by Mrp2 in Vivo: Studies UsingMrp2(Abcc2) Knockout Mice

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