The role of nuclear receptors in pharmacokinetic drug–drug interactions in oncology

doi:10.1016/j.ctrv.2007.02.003

Cancer Treatment Reviews

Volume 33, Issue 4, June 2007, Pages 369-380

https://doi.org/10.1016/j.ctrv.2007.02.003 Get rights and content

Summary

Drug–drug interactions can have a major impact on treatment outcome in cancer patients. These patients are at high risk of such interactions, because they are treated with combinations of multiple cytotoxic anticancer drugs or hormonal agents often co-administered with prophylactic antiemetics and analgesics to provide palliation. Interactions between drugs can affect the pharmacokinetics of concomitantly administered chemotherapeutic agents. Especially, due to the specific properties of anticancer drugs, such as a narrow therapeutic index and steep dose–toxicity curve, small pharmacokinetic changes can have significant clinical consequences like decreased therapeutic efficacy or increased toxicity. An important mechanism that underlies these interactions is the induction of enzymes or efflux transporters involved in the biotransformation and clearance of anticancer drugs. Several nuclear receptors, like the pregnane X receptor (PXR), constitutively androstane receptor (CAR), have been shown to regulate induction. Activation of these receptors will lead to induction of important enzymes like cytochrome P450 3A4 (CYP3A4), which is involved in the biotransformation of more than 50% of all clinically used drugs. Therefore, concomitant administration of agents that activate PXR will affect the pharmacokinetics of drugs that are substrate for PXRs target genes, which include CYP3A4 and MDR-1. Understanding of the molecular mechanisms that underlie enzyme induction and the identification of (new) drugs involved in pharmacokinetic drug–drug interactions may contribute to the predictability of drug–drug interactions and eventually help to develop safer anticancer regimens.

Introduction

One of the major obstacles in predicting the treatment outcome in cancer patients in terms of efficacy and toxicity is the large intra- and interindividual pharmacokinetic variability of chemotherapy. Because of the specific properties of anticancer drugs, like a narrow therapeutic index and a steep dose–toxicity curve, small changes in the pharmacokinetic profile can significantly alter the clinical response to these drugs.1, 2 Multiple factors are known to be responsible for the interindividual differences in the pharmacokinetic profile of antineoplastic agents such as age, sex, genetic polymorphisms in biotransformation and drug transport, disease status and environmental determinants. However, a substantial part of the pharmacokinetic variability in oncology is caused by drug–drug interactions. Overall, drug–drug interactions are estimated to be responsible for 20–30% of all adverse drug reactions,³ and the risk of clinically significant drug–drug interactions increases with the number of concomitantly administered agents. This is especially relevant in oncology, where the treatment of cancer often constitutes combinations of multiple cytotoxic anticancer drugs. To reduce side effects or to provide palliation, anticancer treatment is also regularly supplemented with supportive medication like prophylactic antiemetics, corticosteroids, anticoagulants, analgesics, antibiotics and anticonvulsants. Furthermore, elderly cancer patients often use drugs for the treatment of other comorbidities, such as diabetes, cardiovascular diseases, mood disturbances, and peptic complaints. In addition, up to 63% of all cancer patients have been reported to use over-the-counter drugs, nutritional supplements and complementary alternative medicines (CAM),⁴ which further increases the risk of clinically relevant drug interactions.⁵

Many pharmacokinetic drug–drug interactions are not recognized as such, because they are mistaken for symptoms of the disease, or, due to the specific properties of anticancer drugs, a certain amount of toxicity is accepted.⁶ In addition, due to the use of combination regimens, the specific agent(s) causing the interaction often cannot be identified. This review explores the clinical implications of pharmacokinetic drug–drug interactions in oncology and discusses the molecular mechanisms involved in these interactions, with a special focus on nuclear receptors. Understanding of the mechanisms underlying nuclear receptor mediated drug–drug interactions may eventually help to predict and manage adverse drug reactions, which may lead to safer and more efficious anticancer regimens.

Section snippets

Pharmacokinetic drug–drug interactions

Drug–drug interactions are generally categorized into pharmacokinetic, pharmacodynamic and pharmaceutical interactions. In oncology these interactions can occur between anticancer drugs, when administered as a combination, or between anticancer drugs and other concomitantly administered drugs, herbs or food components. When one drug alters the absorption, distribution, metabolism or excretion (ADME) of another drug, this interaction is defined as a pharmacokinetic interaction. One of the main

Molecular mechanism of induction

Until recently, the mechanisms behind enzyme induction were unclear. However, in the late 1990s several new orphan receptors like the pregnane X receptor (PXR; NR1I2)¹² and the constitutive androstane receptor (CAR; NR1I3)¹³ were discovered. These receptors belong to the family of ligand-activated transcription factors, known as nuclear receptors, that also include other important drug targets such as the glucocorticoid receptor (GR; NR3C1) and the vitamin D receptor (VDR, NR1I1).

The pregnane X

Methods

Before the discovery of the X receptors, the inductive capacity of compounds was based on data obtained from animal tests and primary cultures of human hepatocytes. However, both models have major drawbacks. An important factor that compromises the use of induction data obtained from in vivo or in vitro animal tests is the marked interspecies differences. The PXR–LBDs of common laboratory animals only have an approximate homology of about 70% with human PXR–LBD, resulting in a high interspecies

Nuclear receptors in oncological drug–drug interactions

It has become clear that the nuclear receptors PXR and CAR regulate the induction of many drug-metabolizing enzymes and drug transporters, many of which are involved in the biotransformation and clearance of widely used anticancer drugs. Activation of PXR and CAR has been associated with clinically important drug–drug interactions. The best-characterized examples that illustrate the clinical significance of both PXR and CAR in oncological drug–drug interactions are those that involve

Conclusion

The role of PXR and CAR, as key mediators of an elaborate network of genes involved in the detoxification and clearance of (anticancer) drugs has become clear. Administration of PXR activating (anticancer) drugs can impact the pharmacokinetic profile of concomitantly given anticancer drugs due to the induction of enzymes and efflux transporters involved in their clearance. Because of the pharmacological properties of anticancer drugs, altered pharmacokinetics often lead to decreased therapeutic

Disclosure of potential conflicts of interests

The authors declare that they have no competing interests.

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Laboratory–Clinical InterfaceThe role of nuclear receptors in pharmacokinetic drug–drug interactions in oncology

Summary

Introduction

Section snippets

Pharmacokinetic drug–drug interactions

Molecular mechanism of induction

Methods

Nuclear receptors in oncological drug–drug interactions

Conclusion

Disclosure of potential conflicts of interests

Lancet Oncol

Cell

J Biol Chem

FEBS Lett

J Biol Chem

Hepatology

J Mol Biol

J Biol Chem

J Biol Chem

J Biol Chem

Hepatology

Toxicol Appl Pharmacol

Lancet

Arch Biochem Biophys

Biochem Pharmacol

Toxicol Appl Pharmacol

J Biol Chem

Clinical-pharmacological strategies to assess drug interaction potential during drug development

Drug Safety

Drug–drug interactions in medical patients: effects of in-hospital treatment and relation to multiple drug use

Int J Clin Pharmacol Ther

Herbal remedies in the United States: potential adverse interactions with anticancer agents

J Clin Oncol

Herb–drug interactions in oncology: focus on mechanisms of induction

Oncologist

Cancer chemotherapy: the promise and the pitfalls

Clin Cancer Res

Effect of cytochrome P450 3A4 inhibition on the pharmacokinetics of docetaxel

Clin Pharmacol Ther

Oral delivery of taxanes

Invest New Drugs

Oxidative metabolism of cyclophosphamide: identification of the hepatic monooxygenase catalysts of drug activation

Cancer Res

Significant induction of cyclophosphamide and thiotepa metabolism by phenytoin

Cancer Chemother Pharmacol

A new orphan member of the nuclear hormone receptor superfamily that interacts with a subset of retinoic acid response elements

Mol Cell Biol

The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions

J Clin Invest

The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux

Nat Med

Animal models of xenobiotic receptors

Curr Drug Metab

Nuclear pregnane X receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification

Mol Pharmacol

Phenytoin induction of the Cyp2c37 gene is mediated by the constitutive androstane receptor

Drug Metab Dispos

Nuclear receptor, pregname X receptor, is required for induction of UDP-glucuronosyltranferases in mouse liver by pregnenolone-16 alpha-carbonitrile

Drug Metab Dispos

The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution

Mol Endocrinol

Humanized xenobiotic response in mice expressing nuclear receptor SXR

Nature

In vivo activation of human pregnane X receptor tightens the blood–brain barrier to methadone through P-glycoprotein up-regulation

Mol Pharmacol

Regulation of the human CYP2B6 gene by the nuclear pregnane X receptor

Mol Pharmacol

Human CYP2C8 is transcriptionally regulated by the nuclear receptors constitutive androstane receptor, pregnane X receptor, glucocorticoid receptor, and hepatic nuclear factor 4alpha

Mol Pharmacol

Induction of human CYP2C9 by rifampicin, hyperforin, and phenobarbital is mediated by the pregnane X receptor

J Pharmacol Exp Ther

Regulation of a xenobiotic sulfonation cascade by nuclear pregnane X receptor (PXR)

Proc Natl Acad Sci USA

Control of steroid, heme, and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor

Proc Natl Acad Sci USA

Expression of constitutive androstane receptor splice variants in human tissues and their functional consequences

J Pharmacol Exp Ther

The nuclear orphan receptor CAR–retinoid X receptor heterodimer activates the phenobarbital-responsive enhancer module of the CYP2B gene

Mol Cell Biol

Phenobarbital-responsive nuclear translocation of the receptor CAR in induction of the CYP2B gene

Laboratory–Clinical Interface
The role of nuclear receptors in pharmacokinetic drug–drug interactions in oncology