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The Oral Route for the Administration of Cytotoxic Drugs: Strategies to Increase the Efficiency and Consistency of Drug Delivery

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Abstract

There is an increasing interest to administer cytotoxic drugs topatients by the oral route. Quality of life issues, treatmentadvantages and pharmaco-economics are major arguments in favorof oral therapy. However, low or moderate bioavailability incombination with considerable interpatient variability arefrequently observed which may reduce the feasibility of the oralroute for this class of drugs with a generally narrow therapeuticwindow. Until recently, investigators focused on absorptionenhancers which slightly damage the intestinal surface such assalicylates, methylxantines and surfactants to improve the oralbioavailability of drugs. To date, a shift can be seen towardsmore subtle mechanisms to enhance the absorption. This reviewarticle focuses on two important mechanisms that determine theoral bioavailability of cytotoxic drugs. These include thepresence of drug transporters in the intestinal epitheliumpumping drugs into the intestinal lumen, such as MDR1 typeP-glycoproteins, and first-pass elimination by cytochrome P450isoenzymes (e.g. 3A4 and 3A5) or other enzymes in the intestinesand/or liver. Currently preclinical and clinical studies arebeing performed to explore the feasibility of blocking thesetransporters/enzymes in order to achieve higher and less variablesystemic drug levels after oral dosing. This review gives anupdate of the results of these studies. It is concluded however,that further research to unravel the processes involved in oraldrug uptake is warranted to make the oral route a more efficientand consistent way of drug administration.

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Authors and Affiliations

  1. Department of Clinical Chemistry, The Netherlands

    Heleen A. Bardelmeijer & Olaf van Tellingen

  2. Department of Medical Oncology, The Netherlands Cancer Institute/ Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands

    Jan H.M. Schellens

  3. Division of Drug Toxicology, Faculty of Pharmacy, Utrecht University, Utrecht, The Netherlands

    Jan H.M. Schellens & Jos H. Beijnen

  4. Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands

    Jos H. Beijnen

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  1. Heleen A. Bardelmeijer
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  2. Olaf van Tellingen
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  3. Jan H.M. Schellens
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  4. Jos H. Beijnen
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Bardelmeijer, H.A., van Tellingen, O., Schellens, J.H. et al. The Oral Route for the Administration of Cytotoxic Drugs: Strategies to Increase the Efficiency and Consistency of Drug Delivery. Invest New Drugs 18, 231–241 (2000). https://doi.org/10.1023/A:1006469621561

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