Pharmacogenetic Pathway Analysis for Determination of Sunitinib-Induced Toxicity

Erp, Nielka P. van; Eechoute, Karel; Veldt, A. A. van der; Haanen, John B.A.G.; Reyners, An; Mathijssen, Ron H.J.; Boven, Epie; Straaten, Tahar van der; Baak-Pablo, Reneé; Wessels, Judith A.M.; Guchelaar, Henk‐Jan; Gelderblom, Hans

doi:10.1200/jco.2008.21.7679

Cited by 172 publications

(125 citation statements)

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“…(31) Although F431L-BCRP had lower transporter activity than wild-type BCRP, this mutant BCRP still conferred significant drug-resistance in both PA317 and K562 cells, so that we should pay attention to functional relevance between drug-drug interaction and this mutant BCRP. Importantly, our findings demonstrate that germ-line mutations of the BCRP ⁄ ABCG2 gene 1291T>C (F431L), affect its pharmacological interaction with sunitinib.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…In addition, this SNP has been associated with increased plasma exposure to erlotinib [41] and higher risk for the development of gefitinib [42] and sunitinib [43] induced toxicity/ adverse events. The fact that an association between the rs2622604 genotype and statin kinetics was identified in this work is of particular importance, as up to now most of the BCRP-related pharmacogenetic research in this class of drugs focuses on the effects of the c.421C>A polymorphism.…”

Section: Discussionmentioning

confidence: 99%

Modelling of atorvastatin pharmacokinetics and the identification of the effect of a BCRP polymorphism in the Japanese population

Tsamandouras

Guo

Wendling

et al. 2017

Pharmacogenetics and Genomics

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Aim(s): Ethnicity has a modulating role in atorvastatin pharmacokinetics, with Asian subjects reported to have higher exposure compared to Caucasians. Therefore, it is difficult to safely extrapolate atorvastatin pharmacokinetic data and models across ethnic groups. This work aims to develop a population pharmacokinetic model for atorvastatin and its pharmacologically active metabolites specifically for the Japanese population. Subsequently it is aimed to identify genetic polymorphisms affecting atorvastatin pharmacokinetics in this population. Methods:Atorvastatin acid and o-OH-atorvastatin acid plasma concentrations, clinical/ demographic characteristics and genotypes for 18 genetic polymorphisms (3, 3, 1, 1, 7, 2 and 1 in the ABCB1, ABCG2, CYP3A4, CYP3A5, SLCO1B1, SLCO2B1 and PPARA genes respectively) were collected from 27 Japanese individuals (taking 10mg atorvastatin once daily) and analysed using a population pharmacokinetics modelling approach. Results:The developed population pharmacokinetic model (one-compartment for atorvastatin acid linked through metabolite formation to an additional compartment describing the disposition of o-OH-atorvastatin acid) accurately described the observed data and the associated population variability. Our analysis suggested that subjects carrying one variant allele for the rs2622604 polymorphism (ABCG2) exhibit a 55% (95%CI: 16%-131%) increase in atorvastatin oral bioavailability relatively to the value in individuals without the variant allele. Conclusion:The current work reports the identification in the Japanese population of a BCRP polymorphism, not previously associated with the pharmacokinetics of any statin, that substantially increases atorvastatin acid and o-OH-atorvastatin acid exposure. The developed model may be of clinical importance in order to guide dosing recommendations tailored specifically for the Japanese.

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“…In addition, studies of individual patient characteristics predisposing for toxicities are promising, because these may lead to optimal treatment strategies. For example, a recent study indicated that polymorphisms in genes encoding metabolizing enzymes, efflux transporters, and drug targets are associated with sunitinib-related toxicities [42].…”

Section: Discussionmentioning

confidence: 99%

Oral Adverse Events Associated with Tyrosine Kinase and Mammalian Target of Rapamycin Inhibitors in Renal Cell Carcinoma: A Structured Literature Review

et al. 2011

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After completing this course, the reader will be able to:1. Describe the oral manifestations that can appear with TKI/mTORI.2. Describe the limitations of the current oral assessment tools in assessing these novel presentations and list items needed to assess the presentations properly.This article is available for continuing medical education credit at CME.TheOncologist.com. CME CMECorrespondence: Christine Boers-Doets, R.N., C.N.S., M. ABSTRACTBackground. Oral adverse events (OAEs) associated with multitargeted tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin inhibitors (mTORIs) are underestimated but frequent and novel presentations of mucosal manifestations. Because optimal antitumor activity requires maintaining the optimal dose, it is essential to avoid unintended treatment delays or interruptions. Methods. We review the reported prevalence and appearance of OAEs with TKIs and mTORIs and the current oral assessment tools commonly used in clinical trials. We discuss the correlations between OAEs and hand-foot skin reaction (HFSR) and rash.Results. The reported prevalence of oral mucositis/stomatitis of any grade is 4% for pazopanib, 28% for sorafenib, 38% for sunitinib, 41% for temsirolimus, and 44% for everolimus. Oral lesions associated with these agents have

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Pharmacogenetic Pathway Analysis for Determination of Sunitinib-Induced Toxicity

Cited by 172 publications

References 32 publications

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

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

Modelling of atorvastatin pharmacokinetics and the identification of the effect of a BCRP polymorphism in the Japanese population

Oral Adverse Events Associated with Tyrosine Kinase and Mammalian Target of Rapamycin Inhibitors in Renal Cell Carcinoma: A Structured Literature Review

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