Lack of Improvement of Oral Absorption of ME3277 by Prodrug Formation Is Ascribed to the Intestinal Efflux Mediated by Breast Cancer Resistant Protein (BCRP/ABCG2)

Kondo, Chihiro; Onuki, Reiko; Kusuhara, Hiroyuki; Suzuki, Hiroshi; Suzuki, Michiko; Okudaira, Noriko; Kojima, Maho; Ishiwata, Kazuya; Jonker, Johan W.; Sugiyama, Yuichi

doi:10.1007/s11095-005-2487-9

Cited by 25 publications

(13 citation statements)

References 14 publications

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“…Abcg2 has been shown to account for the efflux of intracellularly formed glucuronide and sulfate conjugates (E3040 glucuronide, E3040 sulfate, and 4-methylumbelliferone sulfate) [1]; the active form of the ester-type prodrug of ME3277 [38] in the small intestine; the biliary excretion of drugs such as nitrofurantoin [51], methotrexate [10], pitavastatin [25], and salfasalazine [86]; and the urinary excretion of methotrexate [10] and E3040 sulfate [56]. As far as the blood-brain barrier is concerned, the importance of BCRP remains controversial.…”

Section: Abcg2 (Bcrp/abcp/mxr)mentioning

confidence: 99%

ATP-binding cassette, subfamily G (ABCG family)

Kusuhara

Sugiyama

2006

Pflugers Arch - Eur J Physiol

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143

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This review summarizes the characteristics of the ATP-binding cassette, subfamily G (ABCG family), which has five members: ABCG1, ABCG2, ABCG4, ABCG5, and ABCG8. The members consist of a single ABC cassette in the amino terminal followed by six putative transmembrane domains, and to become functionally active, they form homo-or obligate heterodimers. Except for ABCG2, the members of the ABCG family play an important role in efflux transport of cholesterol. Mutations causing a loss of function of ABCG5 or ABCG8 are associated with sitosterolemia characterized by accumulation of phyto-and shellfish sterols. Unlike other members, ABCG2 is not involved in cholesterol efflux, but it exhibits broad substrate specificity to xenobiotic compounds. ABCG2 confers cancer cells resistance to anticancer drugs and plays a critical role in the pharmacokinetics of drugs in the clearance organs and tissue barriers. ABCG2 is also associated with a subpopulation phenotype of stem cells. Genetic polymorphisms of ABCG2 have been suggested to account for the interindividual differences in the pharmacokinetics of drugs.

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Section: Abcg2 (Bcrp/abcp/mxr)mentioning

confidence: 99%

ATP-binding cassette, subfamily G (ABCG family)

Kusuhara

Sugiyama

2006

Pflugers Arch - Eur J Physiol

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143

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“…Because BCRP is expressed on the bile canalicular membrane of hepatocytes as well as the brush-border membrane of enterocytes, trophoblast cells in placenta, and the apical membrane of lactiferous ducts in the mammary gland (Maliepaard et al, 2001), BCRP must also be considered as one of the routes for the biliary excretion of organic anions. Current evidence indicates that BCRP contributes to the membrane transport of some substrates, such as intestinal absorption and transfer to breast milk (Jonker et al, 2000(Jonker et al, , 2002Adachi et al, 2004;Mizuno et al, 2004;Kondo et al, 2005;Merino et al, 2005a). Regarding the involvement of BCRP in biliary excretion, some reports have demonstrated that the biliary excretion of 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine and nitrofurantoin is almost impaired in Bcrp1(Ϫ/Ϫ) mice (van Herwaarden et al, 2003;Merino et al, 2005a) and that the biliary excretion of topotecan and cimetidine is also mainly regulated by Bcrp, considering the gender difference in the hepatic expression level of Bcrp and the plasma concentration profiles (Merino et al, 2005b).…”

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confidence: 99%

Involvement of BCRP (ABCG2) in the Biliary Excretion of Pitavastatin

Hirano¹,

Maeda²,

Matsushima³

et al. 2005

Mol Pharmacol

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233

187

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Pitavastatin, a novel potent 3-hydroxymethylglutaryl coenzyme A reductase inhibitor, is distributed selectively to the liver and excreted into bile in unchanged form in rats. We reported previously that the hepatic uptake is mainly mediated by organic anion transporting polypeptide (OATP) 1B1, whereas the biliary excretion mechanism remains to be clarified. In the present study, we investigated the role of breast cancer resistance protein (BCRP) in the biliary excretion of pitavastatin. The ATP-dependent uptake of pitavastatin by human and mouse BCRP-expressing membrane vesicles was significantly higher compared with that by control vesicles with K m values of 5.73 and 4.77 M, respectively. The biliary excretion clearance of pitavastatin in Bcrp1(Ϫ/Ϫ) mice was decreased to one-tenth of that in control mice. The biliary excretion of pitavastatin was unchanged between control and Eisai hyperbilirubinemic rats, indicating a minor contribution of multidrug resistance-associated protein (Mrp) 2. This observation differs radically from that for a more hydrophilic statin, pravastatin, of which biliary excretion is largely mediated by Mrp2. These data suggest that the biliary clearance of pitavastatin can be largely accounted for by BCRP in mice. In the case of humans, transcellular transport of pitavastatin was determined in the Madin-Darby canine kidney II cells expressing OATP1B1 and human canalicular efflux transporters. A significant basal-to-apical transport of pitavastatin was observed in OATP1B1/MDR1 and OATP1B1/MRP2 double transfectants as well as OATP1B1/BCRP double transfectants, implying the involvement of multiple transporters in the biliary excretion of pitavastatin in humans. This is in contrast to a previous belief that the biliary excretion of statins is mediated mainly by MRP2.

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“…BCRP has been reported to limit the oral availability of topotecan and ME3277, which is produced intracellularly from its ester-type prodrug (Jonker et al, 2002;Kondo et al, 2005). Furthermore, BCRP accepts a variety of sulfate conjugates of xenobiotics as substrates, leading to the hypothesis that Bcrp is involved in the efflux of sulfate conjugates formed intracellularly by SULT.…”

mentioning

confidence: 99%

Regional Expression and Activity of Breast Cancer Resistance Protein (Bcrp/Abcg2) in Mouse Intestine: Overlapping Distribution with Sulfotransferases

Enokizono

Kusuhara²,

Sugiyama³

2007

Drug Metab Dispos

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ABSTRACT:Breast cancer resistance protein (Bcrp/Abcg2) is a member of the ATP-binding cassette transporter family with the ability to transport a variety of sulfate conjugates. In the present study, the regional expression and activity of Bcrp and sulfotransferases (SULTs/Sults) were investigated in mouse intestine. Western blotting analysis revealed the highest expression of Bcrp in the ileum over the duodenum, jejunum, and colon. Functional analysis of Bcrp was performed in everted intestinal sacs using 4-methylumbelliferone (4MU). The mucosal secretion clearance of 4MU sulfate formed in the enterocytes was markedly reduced in the jejunum, ileum, and colon of Bcrp (؊/؊) mice in comparison with wild-type mice, whereas a slight and nonsignificant reduction was observed in the duodenum. The reduction in the mucosal secretion clearance was most marked in the ileum followed by the colon and jejunum. In addition, the mucosal secretion clearance of minoxidil sulfate, an active metabolite of minoxidil, was also significantly reduced in the intestine of Bcrp (؊/؊) mice. The sulfation activity of 4MU was higher in the colon than in the small intestine where glucuronidation activity was somewhat higher than the sulfation activity. Real-time polymerase chain reaction analysis showed that the expression of sulfotransferases, such as Sult1a1/2, Sult1b1, and Sult1d1, was also highest in the colon. These results suggest that Bcrp activity is higher in the mid to lower intestine and that the cooperation of Bcrp and SULT provides an important detoxification pathway, particularly in the colon.

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Lack of Improvement of Oral Absorption of ME3277 by Prodrug Formation Is Ascribed to the Intestinal Efflux Mediated by Breast Cancer Resistant Protein (BCRP/ABCG2)

Abstract: These results suggest that Bcrp1 plays an important role in the intestinal efflux of ME3277 and, probably, PM-10 and PM-11, metabolites of ME3229, and limits its BA after oral administration of ME3229.

Cited by 25 publications

References 14 publications

ATP-binding cassette, subfamily G (ABCG family)

ATP-binding cassette, subfamily G (ABCG family)

Involvement of BCRP (ABCG2) in the Biliary Excretion of Pitavastatin

Regional Expression and Activity of Breast Cancer Resistance Protein (Bcrp/Abcg2) in Mouse Intestine: Overlapping Distribution with Sulfotransferases

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