Drug interactions at the blood-brain barrier: Fact or fantasy?

Abstract

There is considerable interest in the therapeutic and adverse outcomes of drug interactions at the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB). These include altered efficacy of drugs used in the treatment of CNS disorders, such as AIDS dementia and malignant tumors, and enhanced neurotoxicity of drugs that normally penetrate poorly into the brain. BBB- and BCSFB-mediated interactions are possible because these interfaces are not only passive anatomical barriers, but are also dynamic in that they express a variety of influx and efflux transporters and drug metabolizing enzymes. Based on studies in rodents, it has been widely postulated that efflux transporters play an important role at the human BBB in terms of drug delivery. Furthermore, it is assumed that chemical inhibition of transporters or their genetic ablation in rodents is predictive of the magnitude of interaction to be expected at the human BBB. However, studies in humans challenge this well-established paradigm and claim that such drug interactions will be lesser in magnitude but yet may be clinically significant. This review focuses on current known mechanisms of drug interactions at the blood-brain and blood-CSF barriers and the potential impact of such interactions in humans. We also explore whether such drug interactions can be predicted from preclinical studies. Defining the mechanisms and the impact of drug–drug interactions at the BBB is important for improving efficacy of drugs used in the treatment of CNS disorders while minimizing their toxicity as well as minimizing neurotoxicity of non-CNS drugs.

Introduction

Drug–drug interactions (DDIs) have long been recognized as an important cause of alteration in drug efficacy or adverse drug effects (or toxicity), particularly for drugs that have a narrow therapeutic window. Much of the work on DDIs has been focused on changes in absorption, bioavailability or systemic concentration of the drug (Levy et al., 2000). However, it has been increasingly recognized that DDIs can affect the distribution of drugs into a particular compartment (e.g. CNS) with or without affecting their systemic plasma (or blood) concentration. Furthermore, DDIs can result in CNS effects of medications that normally are not targeted to the brain (Endres et al., 2006).

DDIs that involve the CNS can result from 1) changes in plasma concentrations (unbound or total) of at least one of the interacting drugs (pharmacokinetic interactions), 2) changes in drug's effects at target sites or its disposition within the CNS (pharmacodynamic and pharmacokinetic interactions, respectively), or a combination of the two (Table 1). A third source for altered effects of drugs on the CNS resides in the interfaces between plasma and the CNS, namely the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB). By modulating BBB or BCSFB function, a drug can affect the distribution of another drug into the brain, its removal from the brain, or both. In this case, the plasma concentration of the affected drug often remains unchanged, especially when only a small fraction of the dose distributes into the brain. To distinguish between barrier-mediated interactions and those caused by other mechanisms, the concentration of the affected drug should be measured in the CNS, in the presence and the absence of the precipitant drug. In the clinical setting, however, brain concentrations are normally not measured due to technical and ethical reasons. Thus, BBB-based interactions may be overlooked or confused with pharmacodynamic interactions. From the clinical point of view, DDIs that seem to be unexpected could potentially be prevented if their mechanisms are correctly identified.

The aim of this review is to present an overview of currently known mechanisms of drug interactions at blood–brain interfaces and the potential impact of such interactions on CNS drug disposition and effects. Particularly, we will focus on transporter-mediated DDIs. Most of the existing knowledge on DDIs at the BBB is based on studies in animal models, but few clinical studies and case reports are also available. In vitro studies are beyond the scope of this review, but general principles for prediction of DDIs at the human BBB from in vitro studies as well as from studies in animal models are presented. Detailed discussion of BBB structure and function and methodologies for evaluation of brain penetration of drugs are available elsewhere (Langer and Müller, 2004, Redzic and Segal, 2004, Shen et al., 2004, Hawkins and Davis, 2005, Endres et al., 2006, Nicolazzo et al., 2006, Cecchelli et al., 2007, Upton, 2007, Liu et al., 2008).