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Alfred H Schinkel - One of the best experts on this subject based on the ideXlab platform.
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p glycoprotein mdr1 abcb1 and breast cancer resistance protein bcrp ABCG2 limit brain accumulation of the flt3 inhibitor quizartinib in mice
International Journal of Pharmaceutics, 2019Co-Authors: Jing Wang, Irene A Retmana, Rolf W Sparidans, Jos H. Beijnen, Changpei Gan, Maria C. Lebre, Alfred H SchinkelAbstract:Abstract Quizartinib, a second-generation FLT3 inhibitor, is in clinical development for the treatment of acute myeloid leukemia. We studied its pharmacokinetic interactions with the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug metabolizing enzyme CYP3A, using in vitro transport assays and knockout and transgenic mouse models. Quizartinib was transported by human ABCB1 in vitro, and by mouse (m)Abcb1 and mABCG2 in vivo. Upon oral administration, the brain accumulation of quizartinib was 6-fold decreased by mAbcb1 and 2-fold by mABCG2 (together: 12-fold). Unexpectedly, the absence of mAbcb1 resulted in a ∼2-fold lower plasma exposure in Abcb1a/1b−/− and Abcb1a/1b;ABCG2−/− mice, suggesting that loss of mAbcb1 causes compensatory alterations in alternative quizartinib elimination or uptake systems. mAbcb1 and mABCG2 themselves did not appear to restrict quizartinib oral availability. Oral and intravenous pharmacokinetics of quizartinib were not substantially altered between wild-type, Cyp3a knockout and CYP3A4-humanized mice. All three strains showed relatively high (33–51%) oral bioavailability. If this also applies in humans, this would suggest a limited risk of CYP3A-related inter-individual variation in exposure for this drug. Our results provide a possible rationale for using pharmacological ABCB1/ABCG2 inhibitors together with quizartinib when treating malignant lesions situated in part or in whole behind the blood-brain barrier.
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P-glycoprotein (MDR1/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2) limit brain accumulation of the FLT3 inhibitor quizartinib in mice
International Journal of Pharmaceutics, 2018Co-Authors: Jing Wang, Irene A Retmana, Rolf W Sparidans, Jos H. Beijnen, Changpei Gan, Maria C. Lebre, Alfred H SchinkelAbstract:Abstract Quizartinib, a second-generation FLT3 inhibitor, is in clinical development for the treatment of acute myeloid leukemia. We studied its pharmacokinetic interactions with the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug metabolizing enzyme CYP3A, using in vitro transport assays and knockout and transgenic mouse models. Quizartinib was transported by human ABCB1 in vitro, and by mouse (m)Abcb1 and mABCG2 in vivo. Upon oral administration, the brain accumulation of quizartinib was 6-fold decreased by mAbcb1 and 2-fold by mABCG2 (together: 12-fold). Unexpectedly, the absence of mAbcb1 resulted in a ∼2-fold lower plasma exposure in Abcb1a/1b−/− and Abcb1a/1b;ABCG2−/− mice, suggesting that loss of mAbcb1 causes compensatory alterations in alternative quizartinib elimination or uptake systems. mAbcb1 and mABCG2 themselves did not appear to restrict quizartinib oral availability. Oral and intravenous pharmacokinetics of quizartinib were not substantially altered between wild-type, Cyp3a knockout and CYP3A4-humanized mice. All three strains showed relatively high (33–51%) oral bioavailability. If this also applies in humans, this would suggest a limited risk of CYP3A-related inter-individual variation in exposure for this drug. Our results provide a possible rationale for using pharmacological ABCB1/ABCG2 inhibitors together with quizartinib when treating malignant lesions situated in part or in whole behind the blood-brain barrier.
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Brain and Testis Accumulation of Regorafenib is Restricted by Breast Cancer Resistance Protein (BCRP/ABCG2) and P-glycoprotein (P-GP/ABCB1)
Pharmaceutical Research, 2015Co-Authors: Anita Kort, Selvi Durmus, Els Wagenaar, Rolf W Sparidans, Jos H. Beijnen, Alfred H SchinkelAbstract:Purpose Regorafenib is a novel multikinase inhibitor, currently approved for the treatment of metastasized colorectal cancer and advanced gastrointestinal stromal tumors. We investigated whether regorafenib is a substrate for the multidrug efflux transporters ABCG2 and ABCB1 and whether oral availability, brain and testis accumulation of regorafenib and its active metabolites are influenced by these transporters. Methods We used in vitro transport assays to assess human (h)ABCB1- or hABCG2- or murine (m)ABCG2-mediated active transport at high and low concentrations of regorafenib. To study the single and combined roles of ABCG2 and Abcb1a/1b in oral regorafenib disposition and the impact of Cyp3a-mediated metabolism, we used appropriate knockout mouse strains. Results Regorafenib was transported well by mABCG2 and hABCG2 and modestly by hABCB1 in vitro . ABCG2 and to a lesser extent Abcb1a/1b limited brain and testis accumulation of regorafenib and metabolite M2 (brain only) in mice. Regorafenib oral availability was not increased in ABCG2 ^ -/- ;Abcb1a/1b ^ -/- mice. Up till 2 h, metabolite M5 was undetectable in plasma and organs. Conclusions Brain and testis accumulation of regorafenib and brain accumulation of metabolite M2 are restricted by ABCG2 and Abcb1a/1b. Inhibition of these transporters may be of clinical relevance for patients with brain (micro)metastases positioned behind an intact blood–brain barrier.
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oral availability and brain penetration of the b rafv600e inhibitor vemurafenib can be enhanced by the p glycoprotein abcb1 and breast cancer resistance protein ABCG2 inhibitor elacridar
Molecular Pharmaceutics, 2012Co-Authors: Selvi Durmus, Els Wagenaar, Rolf W Sparidans, Jos H. Beijnen, Alfred H SchinkelAbstract:Vemurafenib (PLX4032) is a novel tyrosine kinase inhibitor that has clinical efficacy against metastatic melanoma harboring a BRAFV600E mutation. We aimed to establish whether oral availability and brain penetration of vemurafenib could be restricted by the multidrug efflux transporters P-glycoprotein (P-gp/ABCB1) and breast cancer resistance protein (BCRP/ABCG2), as these might limit therapeutic efficacy, especially against brain metastases. In vitro, vemurafenib was efficiently transported by both human ABCB1 and ABCG2, and very efficiently by mouse ABCG2, but not by mouse Abcc2. Upon oral administration of vemurafenib (5 mg/kg), Abcb1a/1b–/– mice had a 1.6-fold increased, ABCG2–/– mice a 2.3-fold increased, and Abcb1a/1b–/–;ABCG2–/– mice a 6.6-fold increased plasma AUC, respectively, compared to wild-type (WT) mice, indicating a marked and additive role of these transporters in limiting vemurafenib oral availability. Brain-to-plasma ratios of vemurafenib (oral, 25 mg/kg) were not increased in ABCG2–/– ...
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P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) Restrict Brain Accumulation of the Active Sunitinib Metabolite N-Desethyl Sunitinib
Journal of Pharmacology and Experimental Therapeutics, 2012Co-Authors: Seng Chuan Tang, Birk Poller, Els Wagenaar, Nienke A G Lankheet, Jos H. Beijnen, Alfred H SchinkelAbstract:N -desethyl sunitinib is a major and pharmacologically active metabolite of the tyrosine kinase inhibitor and anticancer drug sunitinib. Because the combination of N -desethyl sunitinib and sunitinib represents total active drug exposure, we investigated the impact of several multidrug efflux transporters on plasma pharmacokinetics and brain accumulation of N -desethyl sunitinib after sunitinib administration to wild-type and transporter knockout mice. In vitro, N -desethyl sunitinib was a good transport substrate of human ABCB1 and ABCG2 and murine ABCG2, but not ABCC2 or Abcc2. At 5 μM, ABCB1 and ABCG2 contributed almost equally to N -desethyl sunitinib transport. In vivo, the systemic exposure of N -desethyl sunitinib after oral dosing of sunitinib malate (10 mg/kg) was unchanged when Abcb1 and/or ABCG2 were absent. However, brain accumulation of N -desethyl sunitinib was markedly increased (13.7-fold) in Abcb1a / 1b (−/−)/ ABCG2 (−/−) mice, but not in Abcb1a / 1b (−/−) or ABCG2 (−/−) mice. In the absence of the ABCB1 and ABCG2 inhibitor elacridar, brain concentrations of N -desethyl sunitinib were detectable only in Abcb1a / 1b (−/−)/ ABCG2 (−/−) mice after sunitinib administration. Combined elacridar plus N -desethyl sunitinib treatment increased N -desethyl sunitinib plasma and brain exposures, but not brain-to-plasma ratios in wild-type mice. In conclusion, brain accumulation of N -desethyl sunitinib is effectively restricted by both Abcb1 and ABCG2. The effect of elacridar treatment in improving brain accumulation of N -desethyl sunitinib in wild-type mice was limited compared with its effect on sunitinib brain accumulation.
Jos H. Beijnen - One of the best experts on this subject based on the ideXlab platform.
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p glycoprotein mdr1 abcb1 and breast cancer resistance protein bcrp ABCG2 limit brain accumulation of the flt3 inhibitor quizartinib in mice
International Journal of Pharmaceutics, 2019Co-Authors: Jing Wang, Irene A Retmana, Rolf W Sparidans, Jos H. Beijnen, Changpei Gan, Maria C. Lebre, Alfred H SchinkelAbstract:Abstract Quizartinib, a second-generation FLT3 inhibitor, is in clinical development for the treatment of acute myeloid leukemia. We studied its pharmacokinetic interactions with the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug metabolizing enzyme CYP3A, using in vitro transport assays and knockout and transgenic mouse models. Quizartinib was transported by human ABCB1 in vitro, and by mouse (m)Abcb1 and mABCG2 in vivo. Upon oral administration, the brain accumulation of quizartinib was 6-fold decreased by mAbcb1 and 2-fold by mABCG2 (together: 12-fold). Unexpectedly, the absence of mAbcb1 resulted in a ∼2-fold lower plasma exposure in Abcb1a/1b−/− and Abcb1a/1b;ABCG2−/− mice, suggesting that loss of mAbcb1 causes compensatory alterations in alternative quizartinib elimination or uptake systems. mAbcb1 and mABCG2 themselves did not appear to restrict quizartinib oral availability. Oral and intravenous pharmacokinetics of quizartinib were not substantially altered between wild-type, Cyp3a knockout and CYP3A4-humanized mice. All three strains showed relatively high (33–51%) oral bioavailability. If this also applies in humans, this would suggest a limited risk of CYP3A-related inter-individual variation in exposure for this drug. Our results provide a possible rationale for using pharmacological ABCB1/ABCG2 inhibitors together with quizartinib when treating malignant lesions situated in part or in whole behind the blood-brain barrier.
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P-glycoprotein (MDR1/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2) limit brain accumulation of the FLT3 inhibitor quizartinib in mice
International Journal of Pharmaceutics, 2018Co-Authors: Jing Wang, Irene A Retmana, Rolf W Sparidans, Jos H. Beijnen, Changpei Gan, Maria C. Lebre, Alfred H SchinkelAbstract:Abstract Quizartinib, a second-generation FLT3 inhibitor, is in clinical development for the treatment of acute myeloid leukemia. We studied its pharmacokinetic interactions with the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug metabolizing enzyme CYP3A, using in vitro transport assays and knockout and transgenic mouse models. Quizartinib was transported by human ABCB1 in vitro, and by mouse (m)Abcb1 and mABCG2 in vivo. Upon oral administration, the brain accumulation of quizartinib was 6-fold decreased by mAbcb1 and 2-fold by mABCG2 (together: 12-fold). Unexpectedly, the absence of mAbcb1 resulted in a ∼2-fold lower plasma exposure in Abcb1a/1b−/− and Abcb1a/1b;ABCG2−/− mice, suggesting that loss of mAbcb1 causes compensatory alterations in alternative quizartinib elimination or uptake systems. mAbcb1 and mABCG2 themselves did not appear to restrict quizartinib oral availability. Oral and intravenous pharmacokinetics of quizartinib were not substantially altered between wild-type, Cyp3a knockout and CYP3A4-humanized mice. All three strains showed relatively high (33–51%) oral bioavailability. If this also applies in humans, this would suggest a limited risk of CYP3A-related inter-individual variation in exposure for this drug. Our results provide a possible rationale for using pharmacological ABCB1/ABCG2 inhibitors together with quizartinib when treating malignant lesions situated in part or in whole behind the blood-brain barrier.
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Brain and Testis Accumulation of Regorafenib is Restricted by Breast Cancer Resistance Protein (BCRP/ABCG2) and P-glycoprotein (P-GP/ABCB1)
Pharmaceutical Research, 2015Co-Authors: Anita Kort, Selvi Durmus, Els Wagenaar, Rolf W Sparidans, Jos H. Beijnen, Alfred H SchinkelAbstract:Purpose Regorafenib is a novel multikinase inhibitor, currently approved for the treatment of metastasized colorectal cancer and advanced gastrointestinal stromal tumors. We investigated whether regorafenib is a substrate for the multidrug efflux transporters ABCG2 and ABCB1 and whether oral availability, brain and testis accumulation of regorafenib and its active metabolites are influenced by these transporters. Methods We used in vitro transport assays to assess human (h)ABCB1- or hABCG2- or murine (m)ABCG2-mediated active transport at high and low concentrations of regorafenib. To study the single and combined roles of ABCG2 and Abcb1a/1b in oral regorafenib disposition and the impact of Cyp3a-mediated metabolism, we used appropriate knockout mouse strains. Results Regorafenib was transported well by mABCG2 and hABCG2 and modestly by hABCB1 in vitro . ABCG2 and to a lesser extent Abcb1a/1b limited brain and testis accumulation of regorafenib and metabolite M2 (brain only) in mice. Regorafenib oral availability was not increased in ABCG2 ^ -/- ;Abcb1a/1b ^ -/- mice. Up till 2 h, metabolite M5 was undetectable in plasma and organs. Conclusions Brain and testis accumulation of regorafenib and brain accumulation of metabolite M2 are restricted by ABCG2 and Abcb1a/1b. Inhibition of these transporters may be of clinical relevance for patients with brain (micro)metastases positioned behind an intact blood–brain barrier.
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oral availability and brain penetration of the b rafv600e inhibitor vemurafenib can be enhanced by the p glycoprotein abcb1 and breast cancer resistance protein ABCG2 inhibitor elacridar
Molecular Pharmaceutics, 2012Co-Authors: Selvi Durmus, Els Wagenaar, Rolf W Sparidans, Jos H. Beijnen, Alfred H SchinkelAbstract:Vemurafenib (PLX4032) is a novel tyrosine kinase inhibitor that has clinical efficacy against metastatic melanoma harboring a BRAFV600E mutation. We aimed to establish whether oral availability and brain penetration of vemurafenib could be restricted by the multidrug efflux transporters P-glycoprotein (P-gp/ABCB1) and breast cancer resistance protein (BCRP/ABCG2), as these might limit therapeutic efficacy, especially against brain metastases. In vitro, vemurafenib was efficiently transported by both human ABCB1 and ABCG2, and very efficiently by mouse ABCG2, but not by mouse Abcc2. Upon oral administration of vemurafenib (5 mg/kg), Abcb1a/1b–/– mice had a 1.6-fold increased, ABCG2–/– mice a 2.3-fold increased, and Abcb1a/1b–/–;ABCG2–/– mice a 6.6-fold increased plasma AUC, respectively, compared to wild-type (WT) mice, indicating a marked and additive role of these transporters in limiting vemurafenib oral availability. Brain-to-plasma ratios of vemurafenib (oral, 25 mg/kg) were not increased in ABCG2–/– ...
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P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) Restrict Brain Accumulation of the Active Sunitinib Metabolite N-Desethyl Sunitinib
Journal of Pharmacology and Experimental Therapeutics, 2012Co-Authors: Seng Chuan Tang, Birk Poller, Els Wagenaar, Nienke A G Lankheet, Jos H. Beijnen, Alfred H SchinkelAbstract:N -desethyl sunitinib is a major and pharmacologically active metabolite of the tyrosine kinase inhibitor and anticancer drug sunitinib. Because the combination of N -desethyl sunitinib and sunitinib represents total active drug exposure, we investigated the impact of several multidrug efflux transporters on plasma pharmacokinetics and brain accumulation of N -desethyl sunitinib after sunitinib administration to wild-type and transporter knockout mice. In vitro, N -desethyl sunitinib was a good transport substrate of human ABCB1 and ABCG2 and murine ABCG2, but not ABCC2 or Abcc2. At 5 μM, ABCB1 and ABCG2 contributed almost equally to N -desethyl sunitinib transport. In vivo, the systemic exposure of N -desethyl sunitinib after oral dosing of sunitinib malate (10 mg/kg) was unchanged when Abcb1 and/or ABCG2 were absent. However, brain accumulation of N -desethyl sunitinib was markedly increased (13.7-fold) in Abcb1a / 1b (−/−)/ ABCG2 (−/−) mice, but not in Abcb1a / 1b (−/−) or ABCG2 (−/−) mice. In the absence of the ABCB1 and ABCG2 inhibitor elacridar, brain concentrations of N -desethyl sunitinib were detectable only in Abcb1a / 1b (−/−)/ ABCG2 (−/−) mice after sunitinib administration. Combined elacridar plus N -desethyl sunitinib treatment increased N -desethyl sunitinib plasma and brain exposures, but not brain-to-plasma ratios in wild-type mice. In conclusion, brain accumulation of N -desethyl sunitinib is effectively restricted by both Abcb1 and ABCG2. The effect of elacridar treatment in improving brain accumulation of N -desethyl sunitinib in wild-type mice was limited compared with its effect on sunitinib brain accumulation.
Walther Honscha - One of the best experts on this subject based on the ideXlab platform.
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a novel mdckii in vitro model for assessing ABCG2 drug interactions and regulation of ABCG2 transport activity in the caprine mammary gland by environmental pollutants and pesticides
Toxicology in Vitro, 2014Co-Authors: Sandra Halwachs, Louise Wassermann, Walther HonschaAbstract:Abstract The ABC efflux transporter ABCG2 represents the main route for active secretion of xenobiotics into milk. Thus, ABCG2 regulation by aryl hydrocarbon receptor (AhR) ligands including ubiquitously environmental pollutants is of great toxicological relevance. However, no adequate in vitro model is as yet available to study AhR-dependent ABCG2 regulation in dairy animals. In this study, we therefore systematically investigated the effect of various environmental contaminants and pesticides on ABCG2 efflux activity in MDCKII cells stably expressing mammary ABCG2 from dairy goats. The AhR-agonists TCDD, Aroclor 1254, prochloraz, and iprodione caused a dose- and time-dependent increase in EROD activity. Moreover, TCDD and prochloraz significantly stimulated ABCG2 transport activity through a dose- and time-dependent induction of transporter gene expression. AhR inhibitors like CH 223191 significantly reversed TCDD- and prochloraz-induced stimulation of ABCG2 efflux activity. In contrast, non-AhR activators such as PCB 101 had no significant effect on EROD activity, ABCG2 gene expression or transporter activity. As we identified various anthelmintics including monepantel as potential ABCG2 substrates this regulatory mechanism may result in increased milk residues of potentially harmful xenobiotics. Thus, MDCKII-cABCG2 cells may represent a suitable in vitro model to study mammary ABCG2 secretory activity and its potential regulation by AhR-activating contaminants.
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Assessment of ABCG2-mediated transport of xenobiotics across the blood–milk barrier of dairy animals using a new MDCKII in vitro model
Archives of Toxicology, 2013Co-Authors: Louise Wassermann, Sandra Halwachs, Daniela Baumann, Ingo Schaefer, Peter Seibel, Walther HonschaAbstract:The ATP-binding cassette (ABC) efflux transporter ABCG2 represents the main route for active secretion of drugs and toxins across the blood–milk barrier, thereby producing a potential health risk for dairy consumers through formation of relevant residues in milk. However, no suitable in vitro model is as yet available to systematically investigate ABCG2-mediated transport of xenobiotics into milk of dairy animals. We recently cloned ABCG2 from the lactating mammary gland of dairy cows (bABCG2) and goats (cABCG2). Thus, the objective of this study was to generate a suitable blood–milk barrier in vitro model using polarized MDCKII monolayers stably expressing mammary bABCG2 or cABCG2. ABCG2 protein was localized by confocal microscopy to the apical and lateral plasma membrane of polarized MDCKII cells. Intact barrier function of MDCKII-bABCG2 and MDCKII-cABCG2 monolayers was confirmed by determination of cell permeability of transcellular marker propranolol and paracellular marker atenolol which was ≤1 %. In flux assays, ABCG2 substrate 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) showed preferential basolateral to apical (B > A) transport in ABCG2-MDCKII cells. This apically directed PhIP transport was significantly inhibited by ABCG2 inhibitor fumitremorgin C (FTC) or the flavonoid equol. PhIP B > A transport in MDCKII-bABCG2 monolayers was additionally decreased by ABCG2 inhibitor Ko143. The fluoroquinolone antibiotic enrofloxacin was identified as a substrate of ruminant mammary ABCG2. The analgesic drug sodium salicylate was shown to be substrate of bABCG2 but not of cABCG2. Thus, the generated mammary ABCG2-expressing MDCKII cells represent a valuable tool to study active secretion of drugs and toxins into milk.
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Determination of functional ABCG2 activity and assessment of drug-ABCG2 interactions in dairy animals using a novel MDCKII in vitro model.
Journal of pharmaceutical sciences, 2012Co-Authors: Louise Wassermann, Sandra Halwachs, Stefan Lindner, Kerstin U. Honscha, Walther HonschaAbstract:The ATP-binding cassette subfamily G member 2 (ABCG2) transporter is a member of the ATP-binding cassette (ABC) family of efflux carriers that mediates cellular extrusion of various drugs and toxins. In the mammary gland, ABCG2 is expressed at the apical membrane of alveolar epithelial cells and is induced during lactation. It is well established that ABCG2 plays the main role in active secretion of xenobiotics into milk of humans and mice. In contrast, no detailed information is as yet available about functional activity and substrate spectrum of ABCG2 in dairy animals. Therefore, we cloned full-length ABCG2 from bovine, ovine and caprine lactating mammary gland tissues using rapid amplification of complementary DNA (cDNA) ends polymerase chain reaction. The generated full-length ABCG2 cDNA constructs were stably transduced in MDCKII cells. Functional ABCG2 efflux activity was demonstrated with the Hoechst H33342 accumulation assay using the specific ABCG2 inhibitor Ko143. The established ruminant MDCKII-ABCG2 cell culture models in conjunction with the H33342 transport assay showed interaction of various drugs such as cefalexin and albendazole with bABCG2, oABCG2 or cABCG2. Moreover, the flavonoids equol and quercetin exhibited interaction with all ruminant ABCG2 clones. Altogether, our generated cell culture models allowed rapid and high-throughput screening of potential ruminant ABCG2 substrates and thus increase the understanding of carrier-associated secretion of xenobiotics into milk.
Els Wagenaar - One of the best experts on this subject based on the ideXlab platform.
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P-glycoprotein, CYP3A, and Plasma Carboxylesterase Determine Brain Disposition and Oral Availability of the Novel Taxane Cabazitaxel (Jevtana) in Mice
Molecular Pharmaceutics, 2015Co-Authors: Seng Chuan Tang, Anita Kort, Ka Lei Cheung, Selvi Durmus, Els Wagenaar, Jeroen J.m.a. Hendrikx, Hilde Rosing, Tatsuki Fukami, Miki Nakajima, Bart J M Van VlijmenAbstract:We aimed to clarify the roles of the multidrug-detoxifying proteins ABCB1, ABCG2, ABCC2, and CYP3A in oral availability and brain accumulation of cabazitaxel, a taxane developed for improved therapy of docetaxel-resistant prostate cancer. Cabazitaxel pharmacokinetics were studied in Abcb1a/1b, ABCG2, Abcc2, Cyp3a, and combination knockout mice. We found that human ABCB1, but not ABCG2, transported cabazitaxel in vitro. Upon oral cabazitaxel administration, total plasma levels were greatly increased due to binding to plasma carboxylesterase Ces1c, which is highly upregulated in several knockout strains. Ces1c inhibition and in vivo hepatic Ces1c knockdown reversed these effects. Correcting for Ces1c effects, Abcb1a/1b, ABCG2, and Abcc2 did not restrict cabazitaxel oral availability, whereas Abcb1a/1b, but not ABCG2, dramatically reduced cabazitaxel brain accumulation (>10-fold). Coadministration of the ABCB1 inhibitor elacridar completely reversed this brain accumulation effect. After correction for Ces1c ...
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Brain and Testis Accumulation of Regorafenib is Restricted by Breast Cancer Resistance Protein (BCRP/ABCG2) and P-glycoprotein (P-GP/ABCB1)
Pharmaceutical Research, 2015Co-Authors: Anita Kort, Selvi Durmus, Els Wagenaar, Rolf W Sparidans, Jos H. Beijnen, Alfred H SchinkelAbstract:Purpose Regorafenib is a novel multikinase inhibitor, currently approved for the treatment of metastasized colorectal cancer and advanced gastrointestinal stromal tumors. We investigated whether regorafenib is a substrate for the multidrug efflux transporters ABCG2 and ABCB1 and whether oral availability, brain and testis accumulation of regorafenib and its active metabolites are influenced by these transporters. Methods We used in vitro transport assays to assess human (h)ABCB1- or hABCG2- or murine (m)ABCG2-mediated active transport at high and low concentrations of regorafenib. To study the single and combined roles of ABCG2 and Abcb1a/1b in oral regorafenib disposition and the impact of Cyp3a-mediated metabolism, we used appropriate knockout mouse strains. Results Regorafenib was transported well by mABCG2 and hABCG2 and modestly by hABCB1 in vitro . ABCG2 and to a lesser extent Abcb1a/1b limited brain and testis accumulation of regorafenib and metabolite M2 (brain only) in mice. Regorafenib oral availability was not increased in ABCG2 ^ -/- ;Abcb1a/1b ^ -/- mice. Up till 2 h, metabolite M5 was undetectable in plasma and organs. Conclusions Brain and testis accumulation of regorafenib and brain accumulation of metabolite M2 are restricted by ABCG2 and Abcb1a/1b. Inhibition of these transporters may be of clinical relevance for patients with brain (micro)metastases positioned behind an intact blood–brain barrier.
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oral availability and brain penetration of the b rafv600e inhibitor vemurafenib can be enhanced by the p glycoprotein abcb1 and breast cancer resistance protein ABCG2 inhibitor elacridar
Molecular Pharmaceutics, 2012Co-Authors: Selvi Durmus, Els Wagenaar, Rolf W Sparidans, Jos H. Beijnen, Alfred H SchinkelAbstract:Vemurafenib (PLX4032) is a novel tyrosine kinase inhibitor that has clinical efficacy against metastatic melanoma harboring a BRAFV600E mutation. We aimed to establish whether oral availability and brain penetration of vemurafenib could be restricted by the multidrug efflux transporters P-glycoprotein (P-gp/ABCB1) and breast cancer resistance protein (BCRP/ABCG2), as these might limit therapeutic efficacy, especially against brain metastases. In vitro, vemurafenib was efficiently transported by both human ABCB1 and ABCG2, and very efficiently by mouse ABCG2, but not by mouse Abcc2. Upon oral administration of vemurafenib (5 mg/kg), Abcb1a/1b–/– mice had a 1.6-fold increased, ABCG2–/– mice a 2.3-fold increased, and Abcb1a/1b–/–;ABCG2–/– mice a 6.6-fold increased plasma AUC, respectively, compared to wild-type (WT) mice, indicating a marked and additive role of these transporters in limiting vemurafenib oral availability. Brain-to-plasma ratios of vemurafenib (oral, 25 mg/kg) were not increased in ABCG2–/– ...
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P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) Restrict Brain Accumulation of the Active Sunitinib Metabolite N-Desethyl Sunitinib
Journal of Pharmacology and Experimental Therapeutics, 2012Co-Authors: Seng Chuan Tang, Birk Poller, Els Wagenaar, Nienke A G Lankheet, Jos H. Beijnen, Alfred H SchinkelAbstract:N -desethyl sunitinib is a major and pharmacologically active metabolite of the tyrosine kinase inhibitor and anticancer drug sunitinib. Because the combination of N -desethyl sunitinib and sunitinib represents total active drug exposure, we investigated the impact of several multidrug efflux transporters on plasma pharmacokinetics and brain accumulation of N -desethyl sunitinib after sunitinib administration to wild-type and transporter knockout mice. In vitro, N -desethyl sunitinib was a good transport substrate of human ABCB1 and ABCG2 and murine ABCG2, but not ABCC2 or Abcc2. At 5 μM, ABCB1 and ABCG2 contributed almost equally to N -desethyl sunitinib transport. In vivo, the systemic exposure of N -desethyl sunitinib after oral dosing of sunitinib malate (10 mg/kg) was unchanged when Abcb1 and/or ABCG2 were absent. However, brain accumulation of N -desethyl sunitinib was markedly increased (13.7-fold) in Abcb1a / 1b (−/−)/ ABCG2 (−/−) mice, but not in Abcb1a / 1b (−/−) or ABCG2 (−/−) mice. In the absence of the ABCB1 and ABCG2 inhibitor elacridar, brain concentrations of N -desethyl sunitinib were detectable only in Abcb1a / 1b (−/−)/ ABCG2 (−/−) mice after sunitinib administration. Combined elacridar plus N -desethyl sunitinib treatment increased N -desethyl sunitinib plasma and brain exposures, but not brain-to-plasma ratios in wild-type mice. In conclusion, brain accumulation of N -desethyl sunitinib is effectively restricted by both Abcb1 and ABCG2. The effect of elacridar treatment in improving brain accumulation of N -desethyl sunitinib in wild-type mice was limited compared with its effect on sunitinib brain accumulation.
Shailendra B. Patel - One of the best experts on this subject based on the ideXlab platform.
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the atherogenicity of plant sterols the evidence from genetics to clinical trials
Journal of AOAC International, 2015Co-Authors: Oliver Weingartner, Daniel Teupser, Shailendra B. PatelAbstract:: The human diet is naturally varied and contains not only essential nutrients, but also contains molecules that the body actively excludes or minimizes exposure. Among these molecules are xenosterols, of which plant sterols comprise the greatest exposure risk. These sterols comprise approximately 50% of the total sterols we eat, yet we retain <0.5% of these in our bodies. The bulk of this exclusion takes place in the intestine and the heterodimeric transporters ABCG5 and ABCG8 are key to keeping these xenosterols out of our bodies. In normal humans, pharmacological supplementation with plant sterols (and stanols) has been used to lower cholesterol as these impair intestinal absorption/ re-absorption of this molecule; lowering plasma cholesterol has cardiovascular risk benefits. This review challenges whether this intervention is beneficial and may even be harmful. We summarize the evidence involving humans who have genetic disruption of ABCG5/ABCG8 function, from clinical trial data examining plant sterols and cardiovascular risk, from genetic data affecting normal humans and ABCG5/ABCG8 variations to data obtained using animal models. Accumulation of xenosterols in any significant amount is clearly associated with increased toxicity, and data suggest that at even low levels there may be effects. Importantly, there is also a paucity of data showing cardiovascular end-point benefits with plant sterol/stanol supplementation. The summary of evidence highlights not only caution in recommending such strategies to lower plasma cholesterol, but also in investigating how these xenosterols can affect processes ranging from cardiovascular, endocrine, and neurological function.
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abstract 667 ergosterol or brassicasterol accumulations in abcg8 knockout mice do not account for xenosterol toxicity
Arteriosclerosis Thrombosis and Vascular Biology, 2014Co-Authors: Shailendra B. PatelAbstract:Xenosterol accumulation mice deficient in sterolin function leads to significant toxicity, with infertility, decreased body fat accumulation, macrothrombocytopenia, cardiac fibrosis and premature death1,2. Although sitosterol has been shown to have some biological effect in tissue culture, only stigmasterol has been shown to have a potent biological effect, by activating the transcriptional factor, Lxr3. In patients with sitosterolemia, feeding shell-fish sterols led to accumulation of shell-fish sterols in their plasma4, suggesting any xenosterol could accumulate, if fed, to mammals deficient in Abcg5 or Abcg8. Fungi do not utilize cholesterol, but instead use ergosterol as the primary membrane sterol. To delineate whether ergosterol could accumulate in Abcg8 knockout mice, and lead to toxicity, we designed a diet that was supplemented with highly enriched ergosterol (>98% purity) and fed this to Abcg8 knockout mice. Over a 12-week period, both male and female Abcg8 knockout mice fed an ergosterol-enrich...
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A detailed Hapmap of the Sitosterolemia locus spanning 69 kb; differences between Caucasians and African-Americans
BMC Medical Genetics, 2006Co-Authors: Bhaswati Pandit, Starr E Hazard, Derek Gordon, Shailendra B. PatelAbstract:Background Sitosterolemia is an autosomal recessive disorder that maps to the sitosterolemia locus, STSL , on human chromosome 2p21. Two genes, ABCG5 and ABCG8 , comprise the STSL and mutations in either cause sitosterolemia. ABCG5 and ABCG8 are thought to have evolved by gene duplication event and are arranged in a head-to-head configuration. We report here a detailed characterization of the STSL in Caucasian and African-American cohorts. Methods Caucasian and African-American DNA samples were genotypes for polymorphisms at the STSL locus and haplotype structures determined for this locus Results In the Caucasian population, 13 variant single nucleotide polymorphisms (SNPs) were identified and resulting in 24 different haplotypes, compared to 11 SNPs in African-Americans resulting in 40 haplotypes. Three polymorphisms in ABCG8 were unique to the Caucasian population (E238L, INT10-50 and G575R), whereas one variant (A259V) was unique to the African-American population. Allele frequencies of SNPs varied also between these populations. Conclusion We confirmed that despite their close proximity to each other, significantly more variations are present in ABCG8 compared to ABCG5 . Pairwise D' values showed wide ranges of variation, indicating some of the SNPs were in strong linkage disequilibrium (LD) and some were not. LD was more prevalent in Caucasians than in African-Americans, as would be expected. These data will be useful in analyzing the proposed role of STSL in processes ranging from responsiveness to cholesterol-lowering drugs to selective sterol absorption.
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Localization of ABCG5 and ABCG8 proteins in human liver, gall bladder and intestine
BMC Gastroenterology, 2004Co-Authors: Eric Leighton Klett, David B. Adams, Kenneth D Chavin, Shailendra B. PatelAbstract:Background The molecular mechanisms that regulate the entry of dietary sterols into the body and their removal via hepatobiliary secretion are now beginning to be defined. These processes are specifically disrupted in the rare autosomal recessive disease, Sitosterolemia (MIM 210250). Mutations in either, but not both, of two genes ABCG5 or ABCG8, comprising the STSL locus, are now known to cause this disease and their protein products are proposed to function as heterodimers. Under normal circumstances cholesterol, but not non-cholesterol sterols, is preferentially absorbed from the diet. Additionally, any small amounts of non-cholesterol sterols that are absorbed are rapidly taken up by the liver and preferentially excreted into bile. Based upon the defects in sitosterolemia, ABCG5 and ABCG8 serve specifically to exclude non-cholesterol sterol entry at the intestinal level and are involved in sterol excretion at the hepatobiliary level.
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molecular cloning genomic organization genetic variations and characterization of murine sterolin genes abcg5 and abcg8
Journal of Lipid Research, 2002Co-Authors: Kangmo Lu, Hongwei Yu, Yuehua Zhou, Shelley A Sandell, Gerald Salen, Shailendra B. PatelAbstract:Mammalian physiological processes can distinguish between dietary cholesterol and non-cholesterol, retaining very little of the non-cholesterol in their bodies. We have recently identified two genes, ABCG5 and ABCG8, encoding sterolin-1 and -2 respectively, mutations of which cause the human disease sitosterolemia. We report here the mouse cDNAs and genomic organization of Abcg5 and Abcg8. Both genes are arranged in an unusual head-to-head configuration, and only 140 bases separate their two respective start-transcription sites. A single TATA motif was identified, with no canonical CCAT box present between the two genes. The genes are located on mouse chromosome 17 and this complex spans no more than 40 kb. Expression of both genes is confined to the liver and intestine. For both genes, two different sizes of transcripts were identified which differ in the lengths of their 3′ UTRs. Additionally, alternatively spliced forms for Abcg8 were identified, resulting from a CAG repeat at the intron 1 splice-acceptor site, causing a deletion of a glutamine. We screened 20 different mouse strains for polymorphic variants. Although a large number of polymorphic variants were identified, strains reported to show significant differences in cholesterol absorption rates did not show significant genomic variations in Abcg5 or Abcg8.—Lu, K., M-H. Lee, H. Yu, Y. Zhou, S. A. Sandell, G. Salen, and S. B. Patel. Molecular cloning, genomic organization, genetic variations, and characterization of murine sterolin genes Abcg5 and Abcg8.
