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

Abstract

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.