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346 results on '"Wagenaar, Els"'

5. Interplay of OATP1A/1B/2B1 uptake transporters and ABCB1 and ABCG2 efflux transporters in the handling of bilirubin and drugs

Author

Afd Pharmacology, Afd Pharmacoepi & Clinical Pharmacology, Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Li, Wenlong, Sparidans, Rolf W, Wang, Yaogeng, Martins, Margarida L F, de Waart, Dirk R, van Tellingen, Olaf, Song, Ji-Ying, Lebre, Maria C, van Hoppe, Stéphanie, Wagenaar, Els, Beijnen, Jos H, Schinkel, Alfred H, Afd Pharmacology, Afd Pharmacoepi & Clinical Pharmacology, Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Li, Wenlong, Sparidans, Rolf W, Wang, Yaogeng, Martins, Margarida L F, de Waart, Dirk R, van Tellingen, Olaf, Song, Ji-Ying, Lebre, Maria C, van Hoppe, Stéphanie, Wagenaar, Els, Beijnen, Jos H, and Schinkel, Alfred H

Published
2024

8. Natural deletion of mouse carboxylesterases Ces1c/d/e impacts drug metabolism and metabolic syndrome development

Author

Gan, Changpei, primary, Wang, Jing, additional, Wang, Yaogeng, additional, Martínez-Chávez, Alejandra, additional, Hillebrand, Michel, additional, de Vries, Niels, additional, Beukers, Joke, additional, Lebre, Maria C., additional, Wagenaar, Els, additional, Rosing, Hilde, additional, Klarenbeek, Sjoerd, additional, Bleijerveld, Onno B., additional, Song, Ji-Ying, additional, Altelaar, Maarten, additional, Beijnen, Jos H., additional, and Schinkel, Alfred H., additional

Published
2023
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12. Supplementary Figures 1 through 3 and Supplementary Tables 1 through 3 from OATP1A/1B Transporters Affect Irinotecan and SN-38 Pharmacokinetics and Carboxylesterase Expression in Knockout and Humanized Transgenic Mice

Author

Iusuf, Dilek, primary, Ludwig, Marion, primary, Elbatsh, Ahmed, primary, van Esch, Anita, primary, van de Steeg, Evita, primary, Wagenaar, Els, primary, van der Valk, Martin, primary, Lin, Fan, primary, van Tellingen, Olaf, primary, and Schinkel, Alfred H., primary

Published
2023
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14. Natural deletion of mouse carboxylesterases Ces1c/d/e impacts drug metabolism and metabolic syndrome development

Author

Gan, Changpei, Wang, Jing, Wang, Yaogeng, Martínez-Chávez, Alejandra, Hillebrand, Michel, de Vries, Niels, Beukers, Joke, Lebre, Maria C., Wagenaar, Els, Rosing, Hilde, Klarenbeek, Sjoerd, Bleijerveld, Onno B., Song, Ji Ying, Altelaar, Maarten, Beijnen, Jos H., Schinkel, Alfred H., Gan, Changpei, Wang, Jing, Wang, Yaogeng, Martínez-Chávez, Alejandra, Hillebrand, Michel, de Vries, Niels, Beukers, Joke, Lebre, Maria C., Wagenaar, Els, Rosing, Hilde, Klarenbeek, Sjoerd, Bleijerveld, Onno B., Song, Ji Ying, Altelaar, Maarten, Beijnen, Jos H., and Schinkel, Alfred H.

Abstract

Mammalian carboxylesterase 1 enzymes can hydrolyze many xenobiotic chemicals and endogenous lipids. We here identified and characterized a mouse strain (FVB/NKI) in which three of the eight Ces1 genes were spontaneously deleted, removing Ces1c and Ces1e partly, and Ces1d entirely. We studied the impact of this Ces1c/d/e deficiency on drug and lipid metabolism and homeostasis. Ces1c/d/e-/- mice showed strongly impaired conversion of the anticancer prodrug irinotecan to its active metabolite SN-38 in plasma, spleen and lung. Plasma hydrolysis of the oral anticancer prodrug capecitabine to 5-DFCR was also profoundly reduced in Ces1c/d/e-/- mice. Our findings resolved previously unexplained FVB/NKI pharmacokinetic anomalies. On a medium-fat diet, Ces1c/d/e-/- female mice exhibited moderately higher body weight, mild inflammation in gonadal white adipose tissue (gWAT), and increased lipid load in brown adipose tissue (BAT). Ces1c/d/e-/- males showed more pronounced inflammation in gWAT and an increased lipid load in BAT. On a 5-week high-fat diet exposure, Ces1c/d/e deficiency predisposed to developing obesity, enlarged and fatty liver, glucose intolerance and insulin resistance, with severe inflammation in gWAT and increased lipid load in BAT. Hepatic proteomics analysis revealed that the acute phase response, involved in the dynamic cycle of immunometabolism, was activated in these Ces1c/d/e-/- mice. This may contribute to the obesity-related chronic inflammation and adverse metabolic disease in this strain. While Ces1c/d/e deficiency clearly exacerbated metabolic syndrome development, long-term (18-week) high-fat diet exposure overwhelmed many, albeit not all, observed phenotypic differences.

Published
2023

15. Organic anion-transporting polypeptide 2B1 knockout and humanized mice; insights into the handling of bilirubin and drugs

Author

Afd Pharmacoepi & Clinical Pharmacology, Afd Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Pharmacology, Li, Wenlong, Iusuf, Dilek, Sparidans, Rolf W, Wagenaar, Els, Wang, Yaogeng, de Waart, Dirk R, Martins, Margarida L F, van Hoppe, Stéphanie, Lebre, Maria C, van Tellingen, Olaf, Beijnen, Jos H, Schinkel, Alfred H, Afd Pharmacoepi & Clinical Pharmacology, Afd Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Pharmacology, Li, Wenlong, Iusuf, Dilek, Sparidans, Rolf W, Wagenaar, Els, Wang, Yaogeng, de Waart, Dirk R, Martins, Margarida L F, van Hoppe, Stéphanie, Lebre, Maria C, van Tellingen, Olaf, Beijnen, Jos H, and Schinkel, Alfred H

Published
2023

16. Natural deletion of mouse carboxylesterases Ces1c/d/e impacts drug metabolism and metabolic syndrome development

Author

Afd Pharmacoepi & Clinical Pharmacology, Afd Biomol.Mass Spect. and Proteomics, Pharmacoepidemiology and Clinical Pharmacology, Biomolecular Mass Spectrometry and Proteomics, Gan, Changpei, Wang, Jing, Wang, Yaogeng, Martínez-Chávez, Alejandra, Hillebrand, Michel, de Vries, Niels, Beukers, Joke, Lebre, Maria C., Wagenaar, Els, Rosing, Hilde, Klarenbeek, Sjoerd, Bleijerveld, Onno B., Song, Ji Ying, Altelaar, Maarten, Beijnen, Jos H., Schinkel, Alfred H., Afd Pharmacoepi & Clinical Pharmacology, Afd Biomol.Mass Spect. and Proteomics, Pharmacoepidemiology and Clinical Pharmacology, Biomolecular Mass Spectrometry and Proteomics, Gan, Changpei, Wang, Jing, Wang, Yaogeng, Martínez-Chávez, Alejandra, Hillebrand, Michel, de Vries, Niels, Beukers, Joke, Lebre, Maria C., Wagenaar, Els, Rosing, Hilde, Klarenbeek, Sjoerd, Bleijerveld, Onno B., Song, Ji Ying, Altelaar, Maarten, Beijnen, Jos H., and Schinkel, Alfred H.

Published
2023

20. Supplementary Tables 1 - 5 from P-Glycoprotein, CYP3A, and Plasma Carboxylesterase Determine Brain and Blood Disposition of the mTOR Inhibitor Everolimus (Afinitor) in Mice

Author

Tang, Seng Chuan, primary, Sparidans, Rolf W., primary, Cheung, Ka Lei, primary, Fukami, Tatsuki, primary, Durmus, Selvi, primary, Wagenaar, Els, primary, Yokoi, Tsuyoshi, primary, van Vlijmen, Bart J.M., primary, Beijnen, Jos H., primary, and Schinkel, Alfred H., primary

Published
2023
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21. Supplementary Materials and Methods from P-Glycoprotein, CYP3A, and Plasma Carboxylesterase Determine Brain and Blood Disposition of the mTOR Inhibitor Everolimus (Afinitor) in Mice

Author

Tang, Seng Chuan, primary, Sparidans, Rolf W., primary, Cheung, Ka Lei, primary, Fukami, Tatsuki, primary, Durmus, Selvi, primary, Wagenaar, Els, primary, Yokoi, Tsuyoshi, primary, van Vlijmen, Bart J.M., primary, Beijnen, Jos H., primary, and Schinkel, Alfred H., primary

Published
2023
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35. Supplementary Data from Functionally Overlapping Roles of Abcg2 (Bcrp1) and Abcc2 (Mrp2) in the Elimination of Methotrexate and Its Main Toxic Metabolite 7-Hydroxymethotrexate In vivo

Author

Vlaming, Maria L.H., primary, Pala, Zeliha, primary, van Esch, Anita, primary, Wagenaar, Els, primary, de Waart, Dirk R., primary, van de Wetering, Koen, primary, van der Kruijssen, Cornelia M.M., primary, Oude Elferink, Ronald P.J., primary, van Tellingen, Olaf, primary, and Schinkel, Alfred H., primary

Published
2023
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36. Supplementary Figures 1 - 6 from P-Glycoprotein, CYP3A, and Plasma Carboxylesterase Determine Brain and Blood Disposition of the mTOR Inhibitor Everolimus (Afinitor) in Mice

Author

Tang, Seng Chuan, primary, Sparidans, Rolf W., primary, Cheung, Ka Lei, primary, Fukami, Tatsuki, primary, Durmus, Selvi, primary, Wagenaar, Els, primary, Yokoi, Tsuyoshi, primary, van Vlijmen, Bart J.M., primary, Beijnen, Jos H., primary, and Schinkel, Alfred H., primary

Published
2023
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38. Data from Absence of Both Cytochrome P450 3A and P-glycoprotein Dramatically Increases Docetaxel Oral Bioavailability and Risk of Intestinal Toxicity

Author

van Waterschoot, Robert A.B., primary, Lagas, Jurjen S., primary, Wagenaar, Els, primary, van der Kruijssen, Cornelia M.M., primary, van Herwaarden, Antonius E., primary, Song, Ji-Ying, primary, Rooswinkel, Rogier W., primary, van Tellingen, Olaf, primary, Rosing, Hilde, primary, Beijnen, Jos H., primary, and Schinkel, Alfred H., primary

Published
2023
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41. Supplementary Table 1 from Absence of Both Cytochrome P450 3A and P-glycoprotein Dramatically Increases Docetaxel Oral Bioavailability and Risk of Intestinal Toxicity

Author

van Waterschoot, Robert A.B., primary, Lagas, Jurjen S., primary, Wagenaar, Els, primary, van der Kruijssen, Cornelia M.M., primary, van Herwaarden, Antonius E., primary, Song, Ji-Ying, primary, Rooswinkel, Rogier W., primary, van Tellingen, Olaf, primary, Rosing, Hilde, primary, Beijnen, Jos H., primary, and Schinkel, Alfred H., primary

Published
2023
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42. Supplementary Figure 1 from Absence of Both Cytochrome P450 3A and P-glycoprotein Dramatically Increases Docetaxel Oral Bioavailability and Risk of Intestinal Toxicity

Author

van Waterschoot, Robert A.B., primary, Lagas, Jurjen S., primary, Wagenaar, Els, primary, van der Kruijssen, Cornelia M.M., primary, van Herwaarden, Antonius E., primary, Song, Ji-Ying, primary, Rooswinkel, Rogier W., primary, van Tellingen, Olaf, primary, Rosing, Hilde, primary, Beijnen, Jos H., primary, and Schinkel, Alfred H., primary

Published
2023
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44. Carboxylesterase 1 family knockout alters drug disposition and lipid metabolism

Author

Gan, Changpei, primary, Wang, Jing, additional, Martínez-Chávez, Alejandra, additional, Hillebrand, Michel, additional, de Vries, Niels, additional, Beukers, Joke, additional, Wagenaar, Els, additional, Wang, Yaogeng, additional, Lebre, Maria C., additional, Rosing, Hilde, additional, Klarenbeek, Sjoerd, additional, Ali, Rahmen Bin, additional, Pritchard, Colin, additional, Huijbers, Ivo, additional, Beijnen, Jos H., additional, and Schinkel, Alfred H., additional

Published
2022
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49. Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver

Author

van de Steeg, Evita, Stranecky, Viktor, Hartmannova, Hana, Noskova, Lenka, Hrebicek, Martin, Wagenaar, Els, van Esch, Anita, Waart, Dirk R. de, Elferink, Ronald P.J. Oude, Kenworthy, Kathryn E., Sticova, Eva, al-Edreesi, Mohammad, Knisely, A.S., Kmoch, Stanislav, Jirsa, Milan, and Schinkel, Alfred H.

Subjects
Bilirubin -- Physiological aspects -- Genetic aspects -- Research, Hyperbilirubinemia -- Risk factors -- Genetic aspects -- Care and treatment -- Research, Health care industry
Abstract

Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 polymorphisms have previously been linked to drug hypersensitivities. Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b transporters mediate their hepatic reuptake. Transgenic expression of human OATP1B1 or OATP1B3 restored the function of this detoxification-enhancing liver-blood shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this shuttle may allow flexible transfer of bilirubin conjugates (and probably also drug conjugates) formed in upstream hepatocytes to downstream hepatocytes, thereby preventing local saturation of further detoxification processes and hepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia. Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks., Introduction Rotor syndrome (RS; OMIM %237450) is a rare, benign hereditary conjugated hyperbilirubinemia, also featuring coproporphyrinuria and strongly reduced liver uptake of many diagnostic compounds, including cholescintigraphic tracers (1-6). RS [...]

Published
2012
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50. Organic anion transporting polypeptide 1a/1b-knockout mice provide insights into hepatic handling of bilirubin, bile acids, and drugs

Author

Steeg, Evita van de, Wagenaar, Els, van der Kruijssen, Cornelia M.M., Burggraaff, Johanna E.C., de Waart, Dirk R., Oude Elferink, Ronald P.J., Kenworthy, Kathryn E., and Schinkel, Alfred H.

Subjects
Bilirubin -- Properties, Biological transport -- Research, Polypeptides -- Health aspects, Anions -- Properties, Health care industry
Abstract

Organic anion transporting polypeptides (OATPs) are uptake transporters for a broad range of endogenous compounds and xenobiotics. To investigate the physiologic and pharmacologic roles of OATPs of the 1A and 1B subfamilies, we generated mice lacking all established and predicted mouse Oatp1a/1b transporters (referred to as Slco1a/[1b.sup.-/-] mice, as SLCO genes encode OATPs). Slco1a/[1b.sup.-/-] mice were viable and fertile but exhibited markedly increased plasma levels of bilirubin conjugated to glucuronide and increased plasma levels of unconjugated bile acids. The unexpected conjugated hyperbilirubinemia indicates that Oatp1a/ 1b transporters normally mediate extensive hepatic reuptake of glucuronidated bilirubin. We therefore hypothesized that substantial sinusoidal secretion and subsequent Oatp1a/1b-mediated reuptake of glucuronidated compounds can occur in hepatocytes under physiologic conditions. This alters our perspective on normal liver functioning. [Slco1a/[1b.sup.-/-] mice also showed drastically decreased hepatic uptake and consequently increased systemic exposure following i.v. or oral administration of the OATP substrate drugs methotrexate and fexofenadine. Importantly, intestinal absorption of oral methotrexate or fexofenadine was not affected in [Slco1a/[1b.sup.-/-] mice. Further analysis showed that rifampicin was an effective and specific Oatp1a/1b inhibitor in controlling methotrexate pharmacokinetics. These data indicate that Oatp1a/1b transporters play an essential role in hepatic reuptake of conjugated bilirubin and uptake of unconjugated bile acids and drugs. Slco1a/[1b.sup.-/-] mice will provide excellent tools to study further the role of Oatp1a/1b transporters in physiology and drug disposition., Introduction Organic anion transporting polypeptides (human: OATP, gene SLCO; rodents: Oatp, gene Slco) belong to the superfamily of the solute carrier class of organic anion transporters (1). This OATP/ Oatp [...]

Published
2010
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