For psychotropic drugs to produce therapeutic effects, they need to reach molecular targets in the brain at an adequate concentration. However, drug levels in the plasma and the brain differ markedly from each other. This renders the outcome of psychiatric pharmacotherapy uncertain and highly variable from patient to patient on any given dose. A deeper understanding of the mechanisms underlying this disconnect is crucial for personalization of drug therapy and development of new treatment modalities for patients whose disorders are refractory to standard doses of drugs or drug combinations.
In this article, we discuss recent advances in drug transporters and nutrient-transporter interactions that can impact drug bioavailability in the systemic circulation and the brain.1-6 We also present emerging research strategies that may facilitate the discovery and clinical development of predictive diagnostic tests to identify patients at risk for treatment resistance.
As the focus of biomedicine and public health shifts toward the prediction of future disease susceptibilities and treatment outcomes, a new field of predictive (or preemptive) medicine is rapidly emerging with the availability of molecular diagnostic tests in the clinic.7-11 This also blurs the meanings and boundaries between health and disease as well as response and resistance to drug therapy.12 Hence, we suggest ways in which bioscience and bioethics research can be synchronized in predictive medicine.
P-Glycoprotein and drug efflux: a neglected mechanism for treatment resistance
The movement of intravascular compounds from the blood to the brain parenchyma is impeded by the blood-brain barrier (BBB), which is made up of endothelial cells, pericytes, the end-feet of astrocytes, and interendothelial tight junctions. In addition, those molecules that actually penetrate the BBB are subject to extraction from the brain back into the systemic circulation by drug transporters. From an evolutionary standpoint, these biological processes make sense: they ensure that the brain and other tissues essential for life and survival are clear of foreign chemicals and environmental toxins. But they al-so present a formidable challenge to achieving adequate and sustained drug exposure in the brain.
P-glycoprotein (P-gp) is a 170-kDa transmembrane protein and a member of the adenosine triphosphate-binding cassette superfamily of cell membrane transporters. Localized in specialized cells that serve as a barrier between tissue compartments (eg, in intestinal tissue, hepatocytes in the liver), P-gp serves as a functional complement to the physical BBB.2,3 P-gp is expressed as an efflux pump in a polarized manner on endothelial cells lining the cerebral microvasculature and actively removes drugs from the brain, thereby leading to a net reduction in drug availability in the brain tissue (Figure 1).2
A very active P-gp transporter could potentially result in diminished drug delivery to the brain and, by extension, can lead to treatment resistance even though peripheral drug concentrations may appear to be within a therapeutic range.2,3 The relevance of P-gp for psychotropic drug response is not merely theoretical but is supported by recent empirical research.13-15 For example, olanzapine, risperidone, and particularly 9-OH risperidone belong to the growing list of substrates for P-gp.14,15 After intraperitoneal injection of risperidone to abcb1ab-/- P-gp knockout mice, the brain:plasma concentration ratio for risperidone and 9-OH-risperidone was markedly elevated (compared with wild-type mice) in vivo, 12- and 29-fold, respectively.15 These preclinical observations suggest that P-gp may limit the availability of certain second generation antipsychotics in the brain with important ramifications for patients who do not respond within the conventional dosage range despite pharmacotherapy adherence.14,15
At the intestinal level, P-gp mediates the active transport of drugs back into the intestinal lumen, resulting in decreased oral bioavailability of drugs.4,16 In the liver, P-gp contributes to efflux of drugs into the bile, thereby eliminating drugs from the body. A broad range of drugs—HIV protease inhibitors, cardiac glycosides, immunosuppressant agents, antifungals, statins, dietary supplements used in treatment of mental illness (eg, St John's wort), and nutrients (eg, grapefruit juice)—can interact with P-gp by virtue of being a substrate, inhibitor, and/or inducer of this clinically important transporter.1,4-5,16-17 Thus, interindividual and intraindividual variations in P-gp activity, either constitutively or through interactions with drugs and bioactive food constituents, may affect the extent of drug absorption from the intestine and the penetration of psychotropic drugs into the brain.
Interestingly, the ultrarapid activity of other pharmacokinetic pathways, such as the drug metabolizing enzyme cytochrome P-450 2D6 (CYP2D6), is known to increase the risk of treatment resistance.18,19 By contrast, interindividual or population-to-population variability in drug transporter function has received relatively little attention to date in debates on refractoriness to psychiatric pharmacotherapy. The initial research interest in P-gp was due to its expression in cancer cells, removing antitumor drugs from the intracellular to the extracellular space, and thereby conferring a multi-drug resistance phenotype to cancerous tissue. Subsequently, it became clear that P-gp occurs physiologically in healthy tissues, which broadened P-gp's relevance for clinical pharmacology and therapeutics.
Along with academics, the pharmaceutical industry is investing in developing compounds that modulate P-gp function to target and optimize drug delivery to cancers or physiologically/ anatomically isolated tissue compartments. An increase in permeability of the BBB by inhibition of P-gp also offers the promise of administering lower oral doses that may help reduce peripheral psychotropic drug exposure and toxicity. The idea of using P-gp as a site of therapeutic intervention is not new, however, and has been proposed in the literature.13-15
OATP1A2 and grapefruit juice interactions
Although the recognition of P-gp mediated drug transport provides an insight into the disconnect between plasma and brain drug concentrations, there are several conceptual and practical challenges before tangible therapeutic applications in treatment refractory patients can be realized. These caveats include the following:
- There are often multiple drug transporters present across biological barriers such as the BBB.
- Variability in direction of transport (eg, drug influx or efflux) can result in functional antagonism or synergy when 2 or more transporters with similar substrate selectivity are expressed in the same tissue.
- Broad selectivity in substrates and inhibitors may result in overlaps between transporters and with drug metabolism pathways (eg, CYP3A and P-gp markedly overlap in their substrates and inhibitors).
- For many drug transporters, functional expression at the BBB and in different regions of the brain and spatial organization in endothelial cell membranes require further characterization.
- Lack of selective substrates and inhibitors is a major barrier to our ability to characterize population level variability in transporter function in vivo and to design interventions that result in selective modulation of transporter activity without impact on overlapping pathways (eg, consider the previously noted example of CYP3A and P-gp).
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