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Pharmacology: Alfred Schinkel

AlfredSchinkel.jpg

Alfred Schinkel, Ph.D.Group leader

About Alfred Schinkel

Alfred Schinkel

Our research focuses on genes and proteins that affect drug resistance or drug susceptibility in tumors, or influence the pharmacological and toxicological behavior of anticancer and other drugs and toxins, including carcinogens, in mice and man. Insight into these systems may:

  • Improve chemotherapy/pharmacotherapy approaches for cancer and other diseases
  • Increase understanding of risks and opportunities of drug-drug interactions mediated through these systems
  • Increase insight into factors determining susceptibility to toxins and carcinogens
  • Allow elucidation of physiological functions

To study the roles of the proteins involved, and their interactions, we generate and analyze knockout and transgenic mice for the relevant genes as well as appropriate in vitro systems. Most of the studied proteins can be profoundly inhibited or induced by pharmacological modulators. This affords a window of opportunity to modulate these systems to improve pharmacotherapy, but it also involves the risk of adverse drug-drug interactions. 

Active drug efflux transporters
Plasma membrane proteins of the ATP binding cassette (ABC) multidrug transporter family, including P-glycoprotein (P-gp, ABCB1), MRP2 (ABCC2) and BCRP (ABCG2), can actively export a wide range of anticancer and other drugs from cells. These proteins can cause multidrug resistance in tumor cells, and significantly influence the pharmacokinetics of many drugs, including oral availability and tissue penetration. Interindividual variation in activity of these proteins can occur due to genetic polymorphisms, and due to extensive inhibition with various compounds, which can dramatically affect toxicity and therapeutic application of drugs. Analysis of P-gp, Bcrp and Mrp2 knockout mice generated by us has yielded a wealth of information on these functions, and some insights have resulted in ongoing clinical trials in patients to optimize oral pharmacokinetics of anticancer drugs (collaboration with Schellens and Beijnen). We are currently studying overlapping physiological, pharmacological and toxicological functions of these proteins in various compound knockout mouse strains.

Major discoveries we made: 

  • P-gp and BCRP are essential elements of the blood-brain barrier, and keep many drugs out of the brain by pumping them back into the blood. They therefore are major determinants of the clinical use of many drugs, as they avoid their central nervous system (brain) effects. On the other hand, this activity may reduce efficacy of anticancer drugs against brain tumors or micrometastases partly protected by the blood-brain barrier.  
  • P-gp and BCRP can be important factors in limiting the oral availability of many drugs and toxins, as in the intestinal wall they can pump these compounds back into the intestinal lumen. This function limits the clinical use of many drugs, but it also sometimes provides important protection from natural (dietary) toxins.
  • BCRP is an important transporter in the lactating breast, where it transports and even concentrates many drugs, carcinogens and other xenotoxins, but also vitamin B2 (riboflavin) into the milk. It thus contributes to the risk of exposing suckling infants and young to drug and pesticide residues. 
  • BCRP and P-gp expression in the placenta protects the unborn fetus from exposure to drugs, pesticides and toxins present in the bloodstream of the mother. 

Drug-metabolizing enzymes
Arguably the most important factor for variable drug exposure is the Cytochrome P450 3A system (CYP3A), which metabolizes >50% of drugs. CYP3A activity can vary dramatically due to inhibition or induction by co-administered drugs or food components, and is therefore a major factor in drug-drug and drug-food interactions. To assess the in vivo impact of CYP3A, we have generated complete Cyp3a knockout mice, and mice with transgenic overexpression of CYP3A4, the primary human CYP3A enzyme. Analysis of these mice provides insight into the tissue-specific contribution of (human) CYP3A to variable drug exposure and low oral availability of drugs. These insights can be of great value to improve drug administration regimens, but also during the development of optimally efficacious drugs, for cancer and other diseases. We are currently focusing on using the insights obtained to improve the oral bioavailability of taxanes, and testing co-administration regimens to support analogous efforts in patients. 

Important discoveries we made:

  • Intestinal CYP3A activity can be far more important than hepatic CYP3A activity in limiting the oral availability of substrate drugs. 
  • P-gp and CYP3A in the intestine can collaborate efficiently in limiting the oral availability of shared substrate drugs, but they do not have an obvious synergistic mechanism of action in doing so.   

Drug uptake transporters
Many drugs need transport proteins in order to be efficiently taken up into cells. This can affect pharmacokinetically important characteristics, such as uptake of drugs from the intestinal lumen, uptake into the liver or many other tissues, and uptake into tumor cells. Hence, variable activity of the uptake transporters can affect oral availability, elimination rate and route, tissue and tumor distribution of drugs, and therefore therapeutic efficacy and risks of toxic side effects. We generated knockout mice for the organic cation transporter family (Oct/Slc22a1-2), and established its impact on tissue distribution and elimination of anticancer drugs and model compounds. More recently, the importance for drug disposition of multidrug uptake transporters of the organic anion-transporting polypeptide family (OATP/SLCO) has been studied through the generation and characterization of knockout and transgenic mice for the SLCO1A/1B family. We are currently extending this work to additional OATP drug uptake family members.

Major discoveries we made:

  • The human Rotor syndrome, a previously unexplained hereditary conjugated hyperbilirubinemia disorder, is caused by a simultaneous and complete genetic deficiency in two main liver uptake transporters, OATP1B1 and OATP1B3.
  • Efficient detoxification of bilirubin glucuronide by the liver requires functioning of an extrusion-reuptake loop across the basolateral membrane of hepatocytes ("hepatocyte hopping"). 

Clinical translation
Collaborations with the groups of J.H. Beijnen (hospital pharmacist), J.H.M. Schellens (clinical pharmacologist and doctor of internal medicine) and O. van Tellingen at the NKI-AVL allow rapid translation of obtained insights into clinical trials in cancer patients.

Co-workers

Van Hoppe, Stephanie

Stéphanie van Hoppe

PhD student

Experience

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Wang, Jing

Jing Wang

Phd student

Experience

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Wang, Yaogeng

Yaogeng Wang

PhD student

Experience

After graduation from West China Hospital, Sichuan University, I started my PhD in the Netherlands Cancer Institute. My main project aims to investigate the functions of Carboxylesterase 2 metabolizing enzymes on pharmacology, toxicology and physiology, using genetically modified mouse models. I will further use ABC efflux and OATP uptake transporter-modified mouse models, to study the influence of these transporters on the pharmacokinetic behavior of targeted small-molecule anticancer drugs in vivo. The insights and model systems obtained will help us to improve pharmacotherapy of cancer and many other diseases, and to reduce toxicity and carcinogenesis risks.

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Gan, Chanpei

Changpei Gan

PhD student

Experience

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Li

Wenlong Li

Ph.D. student

Experience

My project aims to understand the impact of ABC drug efflux transporters, CYP3A and carboxylesterase drug-metabolizing enzymes on in vivo pharmacology, toxicology and physiology, as well as resistance and susceptibility of tumors to anticancer pharmacotherapy by using genetically modified mouse models. Application of the insights and model systems obtained is used to improve pharmacotherapy of cancer and many other diseases, and reduce toxicity and carcinogenesis risks.

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Martins, Margardia

Margarida Ferreira Martins

Ph.D. student

Experience

I am a motivated human biologist, with expertise in neuroscience, with over 2 years of hands-on experience with in vivo preclinical studies.

After completing my Master's Degree in Neuroscience at the University of Lisbon, I have worked in several Universities and BioTech companies, as well as in a science-communication company.

My PhD project seeks to elucidate what pharmacokinetic factors of opioids can be important determinants of addiction, toxicity, drug-drug interaction risks, and may hamper their safe medical use.

I hope this new knowledge can be translated into clinical applications to improve both current cancer therapy and pharmacotherapy strategies for non-cancer pain.

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Martinez Chavez

Alejandra Martínez Chávez

Ph.D. student

Experience

My research focuses on studying the effect of detoxifying systems, especially drug transporters and drug-metabolizing enzymes, on the behavior of rationally designed (targeted) drugs for cancer therapy. Specifically, I study how these systems affect the pharmacokinetics and tissue distribution of various CDK inhibitors using in vitro and in vivo mouse models. Since reliable drug measurements are essential to perform these studies, my projects also focus on developing new bioanalytical methods, using mostly LC-MS/MS for the quantification of these drugs (and metabolites) in biological matrices. All the insights generated may help to improve pharmacotherapy regimens using these drugs.

 

https://www.researchgate.net/profile/Alejandra_Martinez_Chavez

 

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Key publications View All Publications

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

    J Clin Invest. 2012; 122: 519-28.

    van de Steeg E, Stránecký V, Hartmannová H, Nosková L, Hřebíček M, Wagenaar E, van Esch A, de Waart DR, Oude Elferink RP, Kenworthy KE, Sticová E, al-Edreesi M, Knisely AS, Kmoch S, Jirsa M, Schinkel AH.

    Link to PubMed
  • The breast cancer resistance protein BCRP (ABCG2) concentrates drugs and carcinogenic xenotoxins into milk.

    Nat Med. 2005; 11: 127-9.

    Jonker JW, Merino G, Musters S, van Herwaarden AE, Bolscher E, Wagenaar E, Mesman E, Dale TC, Schinkel AH.

    Link to PubMed
 
 

Recent publications View All Publications

  • P-glycoprotein (MDR1/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2) affect brain accumulation and intestinal disposition of encorafenib in mice

    Pharmacol Res, 2018; 129: 414-423

    Wang J, Gan C, Sparidans RW, Wagenaar E, Van Hoppe S, Beijnen JH, Schinkel AH.

    link to PubMed
  • Hepatic uptake of conjugated bile acids is mediated by both sodium taurocholate cotransporting polypeptide and organic anion transporting polypeptides and modulated by intestinal sensing of plasma bile acid levels in mice

    Hepatology, 2017; 66: 1631-1643.

    Slijepcevic D, Roscam Abbing RLP, Katafuchi T, Blank A, Donkers JM, Van Hoppe S, De Waart DR, Tolenaars D, Van der Meer JHM, Beuers U, Oude Elferink RPJ, Schinkel AH, Van de Graaf SFJ.

    Link to PubMed
 

Contact

  • Office manager

    Lara Spee

  • Telephone Number

    +31 20 512 2035

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