Crossing the Blood-Brain Barrier: Integrating Scientific Innovation With Socio-Ethical Reflection in Predictive Medicine

These complexities represent only a limited portion of the future challenges in drug transporter research.^1-4,16,17 Recent findings concerning the organic anion transporting polypeptide superfamily of transporters (OATPs) further exemplify some of these challenges.⁴ The OATPs transport a broad spectrum of substrates, including endogenous compounds (eg, thyroid hormones, bile acids), and various drugs (eg, digoxin(Drug information on digoxin), pravastatin(Drug information on pravastatin), methotrexate(Drug information on methotrexate), and fexofenadine(Drug information on fexofenadine)). It has recently been found that several drug influx and efflux transporters are expressed in the duodenum.⁵

OATP1A2, formerly thought to be expressed mostly in the brain, is expressed appreciably in the intestine.⁵ OATP1A2 and P-gp proteins colocalize to the apical membrane of the intestinal villi acting in an opposite fashion, increasing and decreasing drug absorption, respectively (Figure 2) [Figure restricted. Please see print edition for content].⁵ In the liver, both of these transporters act in a synergistic manner in hepatocytes to facilitate drug elimination from the body (Figure 2) [Figure restricted. Please see print edition for content].⁴ Recent data indicate that OATP1A2 and P-gp contribute to drug absorption, distribution, and delivery through coordinated effects at multiple tissues. Thus, the clinical consequences of inhibition of P-gp activity at the BBB (eg, to augment drug availability in the brain) can be mitigated or accentuated depending on interindividual variability in OATP1A2 function and respective orientations (ie, as efflux or influx transporters) of P-gp, OATP1A2, and other yet unknown drug transporters in various regions of the brain.

A second set of recent findings concern the interaction of OATP1A2 and grapefruit juice.⁵ It has been observed that coadministration of grapefruit juice and fexofenadine (a substrate for both OATP1A2 and P-gp) results in a 52% decrease in fexofenadine plasma exposure (area under the curve [AUC]); this appears to be consistent with inhibition of OATP1A2-mediated drug uptake in the intestine.⁴ Grapefruit juice consumed 2 hours before administration of fexofenadine produced a lesser effect (38% decrease in AUC) whereas grapefruit juice given 4 hours before fexofenadine did not significantly impact fexofenadine exposure.

The list of psychotropic drugs transported by OATP1A2 is not yet firmly established, but as this information accumulates, it would be essential for clinicians to keep in mind OATP1A2- dependent drug uptake as another mechanism for grapefruit juice-drug interactions. It is not known if long-term ingestion of grapefruit juice and OATP inhibitors impacts drug transport at the BBB in a clinically significant manner. However, limiting grapefruit juice consumption at least 4 hours before the administration of OATP1A2 substrates with a narrow therapeutic window could serve as a clinical guideline to reduce unpredictability in intestinal drug absorption.

While therapeutic optimization of P-gp activity is an exciting area of investigation to improve drug delivery to the brain, we suggest that a singular focus on P-gp may result in unexpected clinical outcomes and even drug toxicity if contributions made by multiple drug transport pathways are neglect- ed. Another challenge is ascertaining whether sustainable or long-term P-gp inhibition can be achieved across the BBB. When P-gp downregulation is achieved successfully, increased functional permeability of the BBB can be problematic in the event of drug overdose and accidental exposure to environmental toxins.

Clinical availability of highly selective and potent P-gp inhibitors is an essential first step to test the therapeutic use and safety of pharmacological interventions that alter BBB permeability.^20-22 Such progress demands substantial time and effort. In the meantime, there is a need to improve the use of existing nonselective P-gp inhibitors for potential clinical applications. A number of clinically available drugs, such as verapamil(Drug information on verapamil) and quinidine(Drug information on quinidine), are P-gp inhibitors. However, these compounds have low potency and also concomitantly impact drug metabolism pathways such as CYP3A or CYP2D6.^20-22 This poses a significant challenge from experimental design and data analysis standpoints. After administration of such nonselective P-gp inhibitors, how do we separate and explain the changes (if there are any) in drug response due to P-gp inhibition at the BBB and inhibition of drug metabolism and attendant increase in peripheral concentrations of P-gp substrate drugs?

Advances in neuroimaging techniques for measurement of receptor occupancy in brain regions outside the BBB (eg, pituitary) may provide a forward lead in this context. For example, the dopamine(Drug information on dopamine) D₂ receptor is expressed in both the basal ganglia and the pituitary. An increase in the ratio of basal ganglia/pituitary D₂ receptor occupancy would lend evidence for an increase in the permeability of the BBB after administration of a P-gp inhibitor. By contrast, this ratio would be anticipated to remain stable or unchanged when a compound inhibits drug metabolism (increasing plasma drug concentrations and thereby brain receptor occupancy) without an appreciable impact on P-gp function at the BBB. The denominator of the basal ganglia/pituitary D₂ receptor occupancy ratio thus could serve to control for changes in plasma drug concentrations after nonselective inhibition of both P-gp and CYP3A.

Although similar ratios are already widely used in preclinical research concerning drug delivery to the brain, measurement of drug occupancy in the pituitary and other regions outside the BBB has not been possible until recently. This technical limitation is being overcome because an increasing number of studies are now able to characterize pituitary receptor occupancy by positron emission tomography.^23,24 The use of this composite metric/ratio as an experimental end point—instead of the absolute measures of drug exposure or receptor occupancy in the brain—may help dissect the overlapping effects of drug transporter inhibitors on P-gp and drug metabolism (eg, CYP3A).

As is evident with the case of drug transporters, an emerging picture in diagnostic and predictive medicine is that an ever-growing list of therapeutically significant molecular pathways is being uncovered. It is anticipated that these advances in basic research will lead to better patient care. However, there are important gaps in the translation of basic science discoveries to clinical practice.^25,26 These gaps in translational research are collectively important enough that in the view of the FDA,²⁵ "The applied sciences needed for medical product development have not kept pace with the tremendous advances in the basic sciences. The new science is not being used to guide the technology development process in the same way that it is accelerating the technology discovery process."

Translational research has the potential to deliver many practical benefits for patients and justify the extensive investments placed by the private and public sector in biomedical research. However, translational research encompasses a complexity of scientific, financial, ethical, regulatory, legislative, and practical hurdles that need to be addressed at several levels to make the process efficient.²⁷ Some have resisted the idea of supporting translational research because of its high costs, particularly in the bench-to-bedside direction of drug development.