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Drug interactions in cancer therapy

Nature Reviews Cancer volume 6, pages 546–558 (2006)Cite this article

A Corrigendum to this article was published on 07 August 2006

Key Points

  • Drug–drug interactions are an important concern in the treatment of cancer. They can affect drug dosage, which is important for optimizing the anti-tumour effect of treatments and minimizing their toxicity to normal tissue.

  • Interactions can occur between drugs and other drugs, food or herbal supplements, and can also be affected by a patient's genetic composition and physiological status. Most pharmacokinetic drug interactions involve drug metabolism and/or transport as a mechanistic basis. Therefore, it is important to understand the role of human enzymes and transporters in the metabolism and disposition of antineoplastic agents, as well as the mechanisms by which antineoplastics modulate the expression and activity of human enzymes and transporters.

  • Pharmacodynamic drug interactions could be the result of overlapping mechanisms of action or combined toxicities to the same target organ. These interactions could be used to increase the therapeutic effect of a combination regimen or to minimize its toxicity.

  • It is important that potential drug interactions are identified early in the drug-development process, and this might be made possible by improvements in in vitro model systems.

Abstract

Drug interactions in oncology are of particular importance owing to the narrow therapeutic index and the inherent toxicity of anticancer agents. Interactions with other medications can cause small changes in the pharmacokinetics or pharmacodynamics of a chemotherapy agent that could significantly alter its efficacy or toxicity. Improvements in in vitro methods and early clinical testing have made the prediction of potentially clinically significant drug interactions possible. We outline the types of drug interaction that occur in oncology, the mechanisms that underlie these interactions and describe select examples.

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Figure 1: Sites of drug disposition.
Figure 2: Metabolism and transport of irinotecan.

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Acknowledgements

This work was supported by the Intramural Research Program of the US National Cancer Institute. This is a US Government work. There are no restrictions on its use. The views expressed within this paper do not necessarily reflect those of the US Government.

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    Charity D. Scripture & William D. Figg

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Glossary

Excipients

Inert substances that are used as diluents or vehicles for drugs.

First-pass effects

The decrease in the bioavailability of an orally administered drug caused by enteric metabolism, hepatic metabolism or elimination before the drug reaches the systemic circulation.

AUC

The area under the curve in a graph of plasma concentration versus time. It is a measure of drug exposure.

Cytochrome P450 enzymes

A membrane-bound family of haem-containing intracellular oxidizing enzymes that are responsible for the first phase of (oxidative) metabolism of many endogenous steroids, hormones and medications. The CYP3A4 isozyme accounts for approximately 70% of the total CYP activity in the intestine.

Substrates

Substrates are metabolized by enzymes and their plasma concentrations are influenced by substances that inhibit or induce their metabolic pathway.

Inhibitor

Inhibitors inactivate specific CYP enzymes in an irreversible way. Metabolism will return to normal once the inhibitor has been removed and new enzymes have been produced.

Inducer

Inducers increase the production of enzymes and therefore accelerate metabolism. Consequently, the plasma levels of substrates are lowered.

P-glycoprotein

A transmembrane protein that is formed by two homologous halves, and which works as an ATP-dependent efflux pump. It is the product of the ATP-binding cassette gene ABCB1, which is also referred to as the multidrug resistance gene MDR1.

Polymorphism

The presence of two or more alleles with a frequency of at least 1% in the general population at the same gene locus.

Induction

Induction means that a substance stimulates the synthesis of an enzyme and metabolic capacity is increased.

Cmax

The highest concentration that a drug reaches in the serum/plasma.

Pharmacogenetics

The study of genetically determined variations in drug response.

Uptake transporters

Membrane-bound proteins that are predominately involved in the movement of substances and/or drugs into the cell.

Efflux transporters

Membrane-bound proteins that are predominately involved in the movement of sustances and/or drugs out of the cell.

Competitive inhibition

Competitive inhibition occurs when two or more drugs compete for the active (binding) site of a single CYP enzyme. This competitive inhibition can decrease the metabolism of one of the drugs, therefore altering its pharmacokinetic behaviour.

Clinically significant drug interactions

Interactions that lead to a change in the therapeutic activity or toxicity of a drug to the extent that dosage adjustment or increased monitoring is necessary.

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Scripture, C., Figg, W. Drug interactions in cancer therapy. Nat Rev Cancer 6, 546–558 (2006). https://doi.org/10.1038/nrc1887

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