Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition in<i>in vitro</i>and<i>in vivo</i>pharmacokinetic studies employing Bcrp1−/−/Mdr1a/1b−/− (triple-knockout) and wild-type mice

Marchetti, Serena; Vries, Nienke A. de; Buckle, Tessa; Bolijn, Maria J.; Eijndhoven, Maria A.J. van; Beijnen, Jos H.; Mazzanti, Roberto; Tellingen, Olaf van; Schellens, Jan H.M.

doi:10.1158/1535-7163.mct-07-2250

Cited by 180 publications

(133 citation statements)

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“…P-gp recognizes drugs with various structures and actions as its substrates (29), suggesting that it has an impact on the pharmacokinetics of a wide range of drugs, which include anticancer drugs, antiepileptic drugs, and immunosuppressive drugs, and that it may contribute to critical adverse events associated with these drugs (30,31). Indeed, several studies have indicated that bioavailability of paclitaxel (32), etoposide (ETP) (33), erlotinib (19), and sorafenib (34), all of which are anticancer drugs and P-gp substrates, are dramatically increased in mice with P-gp deficits after oral administration. Based on substantial evidence, P-gp is recognized as an extremely important factor in the regulation of the pharmacokinetics of drugs used in the clinic.…”

Section: Characterization Of P-gpmentioning

confidence: 99%

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Mechanisms of P-Glycoprotein Alteration During Anticancer Treatment: Role in the Pharmacokinetic and Pharmacological Effects of Various Substrate Drugs

et al. 2014

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Abstract. In clinical pharmacotherapy, therapeutic benefits and adverse effects of medicines differ substantially between individuals and are often determined by their blood levels. Critical regulators influencing the pharmacokinetics and pharmacodynamics of drugs include drug transporters and drug-metabolizing enzymes. Among these, we have focused on P-glycoprotein (P-gp), a drug efflux transporter. A growing body of evidence indicates that the expression and functional activity of P-gp are altered under several pathological conditions, by exposure to substrate drugs of P-gp, and by ingestion of certain foods. In this critical review, we discuss the mechanisms by which anticancer drugs, most of which are P-gp substrates, alter the expression and functional activity of P-gp in tumors and normal tissues after chronic treatment. Accumulating evidence shows that various transcription factors, in addition to epigenetic and post-translational factors, modulate P-gp expression, which alters the pharmacokinetics and pharmacological effects of drugs. Therefore, it is important to consider individual patients with regard to drug-taking history, as well as levels of P-gp expression and function, when providing clinical pharmacotherapy.Keywords: P-glycoprotein, anticancer drug, drug-drug interaction, opioid, cancer *Corresponding author. stoku@pharm.Kobegakuin.ac.jp Published online in J-STAGE on July 2, 2014 doi: 10.1254/jphs.14R01CRInvited article 243 Changes in P-gp by Anticancer Treatment targeted anticancer drugs acting on specific genes or their products has grown rapidly. In fact, combination treatment with molecularly targeted drugs and cytotoxic chemotherapy against cancers such as acute leukemia or lymphatic malignancy improved therapeutic outcome in comparison to conventional anticancer chemotherapy (8, 9). However, solid tumors often have greater inherent resistance and are less sensitive to anticancer drugs (10). Furthermore, chronic exposure to anticancer drugs frequently leads to multi-drug resistance where the therapeutic effects of these drugs on tumors is largely reduced (11). The development of resistance to anticancer chemotherapy remains one of the major obstacles in effective pharmacological therapy for cancer using current treatment strategies (12).Research revealing the role of drug transporters in cancer began with the discovery of P-glycoprotein (P-gp). In 1976, during research to elucidate the mechanism by which cancer cell lines acquire multi-drug resistance, Juliano et al. discovered that P-gp is over-expressed on the surface membranes of multi-drug resistant cancer cells (13). Subsequent studies have demonstrated that P-gp is present in cancer tissue (11,14), as well as in normal tissues such as small intestine, where it regulates drug absorption, and liver and kidney, where it modulates drug clearance (15). These results suggest that P-gp determines blood levels of its substrate drugs. Furthermore, P-gp is now considered to be an extremely important factor in the pharmacokinetics of drugs bec...

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Section: Characterization Of P-gpmentioning

confidence: 99%

“…BCRP, identified from human breast cancer cells exhibiting doxorubicin resistance (17), is involved in the transit of some anticancer drugs such as gefitinib and erlotinib (18,19). The role of BCRP has been well studied, particularly in the small intestine, where it has been shown to alter the absorption of orally administered substrate drugs (20).…”

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confidence: 99%

Mechanisms of P-Glycoprotein Alteration During Anticancer Treatment: Role in the Pharmacokinetic and Pharmacological Effects of Various Substrate Drugs

et al. 2014

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“…However, for a number of tyrosine kinase inhibitors (TKI), including imatinib (2, 3), erlotinib (11), dasatinib (12,13), and lapatinib (14), transport by ABCG2 and P-gp was reported, whereas other TKIs were shown to inhibit ABCG2-and/or P-gp-mediated transport [e.g., gefitinib (15)(16)(17), nilotinib (18,19), and sunitinib (20)]. We therefore anticipated that sorafenib could be a substrate of P-gp and/or ABCG2 as well, and we studied the in vitro transport of sorafenib by human P-gp and ABCG2 and murine Abcg2.…”

Section: Introductionmentioning

confidence: 99%

Breast Cancer Resistance Protein and P-glycoprotein Limit Sorafenib Brain Accumulation

Lagas

Waterschoot

Sparidans

et al. 2010

Molecular Cancer Therapeutics

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Sorafenib is a second-generation, orally active multikinase inhibitor that is approved for the treatment of patients with advanced renal cell carcinoma and patients with unresectable hepatocellular carcinoma. We studied active transport of sorafenib in MDCK-II cells expressing human P-glycoprotein (P-gp/ABCB1) or ABCG2 (breast cancer resistance protein) or murine Abcg2. Sorafenib was moderately transported by P-gp and more efficiently by ABCG2 and Abcg2. Because sorafenib is taken orally, we orally administered sorafenib to wild-type, Abcb1a/1b −/− , Abcg2 −/− , and Abcb1a/1b;Abcg2 −/− mice, completely lacking functional Abcb1a/1b, Abcg2, or both, respectively, and we studied plasma pharmacokinetics and brain accumulation. The systemic exposure on oral administration was not different among all strains. However, brain accumulation was 4.3-fold increased in Abcg2 −/− mice and 9.3-fold increased in Abcb1a/1b;Abcg2 −/− mice. Moreover, when wildtype mice were treated with sorafenib in combination with the dual P-gp and ABCG2 inhibitor elacridar, brain accumulation was similar to that observed for Abcb1a/1b;Abcg2 −/− mice. These results show that the brain accumulation of sorafenib is primarily restricted by ABCG2. This contrasts with previous studies using shared ABCG2 and P-gp substrates, which all suggested that P-gp dominates at the blood-brain barrier, and that an effect of ABCG2 is only evident when both transporters are absent. Interestingly, for sorafenib, it is the other way around, that is, ABCG2, and not P-gp, plays the dominant role in restricting its brain accumulation. Clinically, our findings may be relevant for the treatment of renal cell carcinoma patients with central nervous system relapses, as a dual ABCG2 and P-gp inhibitor might improve the central nervous system entry and thereby the therapeutic efficacy of sorafenib. Mol Cancer Ther; 9(2); 319-26. ©2010 AACR.

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“…Erlotinib is a substrate for Pglycoprotein (P-gp/ABCB1) and breast cancer resistance protein (BRCP/ABCG2). P-gp and BRCP are efflux transporters that negatively regulate intestinal absorption of erlotinib [40]. In patients with genotypes that produce low P-gp or BRCP expression, higher trough concentrations of erlotinib and higher rates of clinical toxicity exist [41,42].…”

Section: Pharmacologymentioning

confidence: 99%

Tyrosine kinase inhibitors for EGFR- and ALK-mutated non-small cell lung cancer

Thompson

Menon

2016

ADMET DMPK

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Discovery of the epidermal growth receptor (EGFR) activating mutations and anaplastic lymphoma kinase (ALK) rearrangements has expanded the therapeutic landscape in non-small cell lung cancer (NSCLC). Survival outcomes for patients with these mutations have improved dramatically with EGFR and ALK tyrosine kinase inhibitors (TKIs). Multiple generations of EGFR and ALK TKIs have been rapidly developed, and patients and clinicians now have several options for first-and second-line treatments. While these small molecule

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Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition inin vitroandin vivopharmacokinetic studies employing Bcrp1−/−/Mdr1a/1b−/− (triple-knockout) and wild-type mice

Cited by 180 publications

References 40 publications

Mechanisms of P-Glycoprotein Alteration During Anticancer Treatment: Role in the Pharmacokinetic and Pharmacological Effects of Various Substrate Drugs

Mechanisms of P-Glycoprotein Alteration During Anticancer Treatment: Role in the Pharmacokinetic and Pharmacological Effects of Various Substrate Drugs

Breast Cancer Resistance Protein and P-glycoprotein Limit Sorafenib Brain Accumulation

Tyrosine kinase inhibitors for EGFR- and ALK-mutated non-small cell lung cancer

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