Diflomotecan pharmacokinetics in relation to ABCG2 421C&gt;A genotype*1

Sparreboom, Alex; Gelderblom, Hans; Marsh, Sharon; Ahluwalia, Ranjeet; Obach, R.; Principe, Paola; Twelves, Chris; Verweij, Jaap; McLeod, Howard L.

doi:10.1016/j.clpt.2004.03.003

Cited by 224 publications

(137 citation statements)

References 19 publications

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“…Heterozygotes exhibited significantly higher plasma concentrations of diflomotecan after intravenous administration, whereas the plasma concentration-time profiles were similar after oral administration [70]. Such a discrepancy cannot be explained from a pharmacokinetic viewpoint, and the effect of such a polymorphism on the plasma concentration should be theoretically clearer after oral administration.…”

Section: Polymorphisms Of Abcg2mentioning

confidence: 89%

ATP-binding cassette, subfamily G (ABCG family)

Kusuhara

Sugiyama

2006

Pflugers Arch - Eur J Physiol

144

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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: Polymorphisms Of Abcg2mentioning

confidence: 89%

ATP-binding cassette, subfamily G (ABCG family)

Kusuhara

Sugiyama

2006

Pflugers Arch - Eur J Physiol

144

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“…ABCB1 appears to be the main paclitaxel transporter 23,24 and variants in ABCB1 have been demonstrated to alter P-glycoprotein expression. 25,26 A nonsynonymous variant in ABCG2 (421C4A; Q141K) has been associated with drug resistance in vitro and in vivo, [27][28][29] and with survival in prostate cancer patients receiving docetaxel chemotherapy (P ¼ 0.05), 30 consequently, despite the lack of evidence associating taxane transport with ABCG2 the 421C4A variant was included in this study.…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetic analysis of paclitaxel transport and metabolism genes in breast cancer

Marsh

Somlo

et al. 2007

Pharmacogenomics J

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Paclitaxel is commonly used in the treatment of breast cancer. Variability in paclitaxel clearance may contribute to the unpredictability of clinical outcomes. We assessed genomic DNA from the plasma of 93 patients with high-risk primary or stage IV breast cancer, who received dose-intense paclitaxel, doxorubicin and cyclophosphamide. Eight polymorphisms in six genes associated with metabolism and transport of paclitaxel were analyzed using Pyrosequencing. We found no association between ABCB1, ABCG2, CYP1B1, CYP3A4, CYP3A5 and CYP2C8 genotypes and paclitaxel clearance. However, patients homozygous for the CYP1B1*3 allele had a significantly longer progression-free survival than patients with at least one Valine allele (P ¼ 0.037). This finding could reflect altered paclitaxel metabolism, however, the finding was independent of paclitaxel clearance. Alternatively, the role of CYP1B1 in estrogen metabolism may influence the risk of invasive or paclitaxel resistant breast cancer in patients carrying the CYP1B1*3 allele.

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“…(14) We also reported variant BCRP SNP cDNAs harboring 421C>A (amino acid substitution Q141K), (15) and this SNP is physiologically important because the pharmacokinetics of diflomotecan, a new camptothecin-derivative anticancer agent, and the risk of adverse reactions, such as gefitinib-induced diarrhea, was affected in patients heterozygous for the A421 allele. (16) In addition, we reported that a germ-line mutant allele 1291T>C expresses the F431L variant of BCRP with lower functional resistance to SN-38. (17) This suggests that amino acid substitution F431L may affect substrate recognition of SN-38.…”

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confidence: 99%

Pharmacological interaction with sunitinib is abolished by a germ‐line mutation (1291T>C) of BCRP/ABCG2 gene

et al. 2010

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Sunitinib malate (Sutent, SU11248) is a small-molecule multitargeted tyrosine kinase inhibitor (TKI) used for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors. Some TKIs can overcome multidrug resistance conferred by ATP-binding cassette transporter, P-glycoprotein (P-gp) ⁄ ABCB1, multidrug resistance-associated protein 1 (MRP1) ⁄ ABCC1, and breast cancer resistance protein (BCRP) ⁄ ABCG2. Here, we analyzed the effects of sunitinib on P-gp and on wild-type and germ-line mutant BCRPs. Sunitinib remarkably reversed BCRP-mediated and partially reversed P-gp-mediated drug resistance in the respective transfectants. The in vitro vesicle transport assay indicated that sunitinib competitively inhibited BCRP-mediated estrone 3-sulfate transport and P-gp-mediated vincristine transport. These inhibitory effects of sunitinib were further analyzed in Q141K-, R482G-, R482S-, and F431L-variant BCRPs. Intriguingly, the F431L-variant BCRP, which is expressed by a germ-line mutant allele 1291T>C, was almost insensitive to both sunitinib-and fumitremorgin C (FTC)-mediated inhibition in a cell proliferation assay. Sunitinib and FTC did not inhibit 125 I-iodoarylazidoprazosin-binding to F431L-BCRP. Thus, residue Phe-431 of BCRP is important for the pharmacological interaction with sunitinib and FTC. Collectively, this is the first report showing a differential effect of a germ-line variation of the BCRP ⁄ ABCG2 gene on the pharmacological interaction between small-molecule TKIs and BCRP. These findings would be useful for improving our understanding of the pharmaceutical effects of sunitinib in personalized chemotherapy. (Cancer Sci 2010; 101: 1493-1500 T he ATP-binding cassette (ABC) transporter proteins, particularly P-glycoprotein (P-gp ⁄ ABCB1), multidrug resistance-associated protein 1 (MRP1 ⁄ ABCC1), and breast cancer resistance protein (BCRP ⁄ MXR ⁄ ABCP ⁄ ABCG2) have been extensively studied as key molecules that are involved in the multidrug-resistant phenotype of cancer cells.(1,2) P-gp effluxes various anticancer agents including vincristine (VCR), paclitaxel (PTX), doxorubicin (DOX), and mitoxantrone (MXR). (1,3) BCRP is referred to as a half-type ABC transporter that functions as a homodimer and transports anticancer agents such as topotecan, irinotecan, SN-38 (7-ethyl-10-hydroxycamptothecin), methotrexate, and MXR out of cells. Many compounds have been tested for their ability to overcome ABC transporter-mediated drug resistance. Verapamil, cyclosporine A (CsA), and other compounds have been identified as inhibitors of P-gp, (5,6) while fumitremorgin C (FTC), tamoxifen derivatives, and certain flavonoids inhibit BCRP.(7-10) Verapamil, for example, directly interacts with P-gp and competitively interferes with transporter-substrate binding. (11) Co-administration of inhibitory compounds would be expected to overcome unwanted anticancer drug resistance during chemotherapy, but is also suspected to affect the pharmacokinetics and pharmacodynamics of substrate anticancer drugs....

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Diflomotecan pharmacokinetics in relation to ABCG2 421C>A genotype*1

Abstract: These findings provide the first evidence linking variant ABCG2 alleles to altered drug exposure and suggest that interindividual variability in substrate drug effects might be influenced, in part, by ABCG2 genotype.

Cited by 224 publications

References 19 publications

ATP-binding cassette, subfamily G (ABCG family)

ATP-binding cassette, subfamily G (ABCG family)

Pharmacogenetic analysis of paclitaxel transport and metabolism genes in breast cancer

Pharmacological interaction with sunitinib is abolished by a germ‐line mutation (1291T>C) of BCRP/ABCG2 gene

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