Role of CNS efflux drug transporters in antiepileptic drug delivery: overcoming CNS efflux drug transport

Abstract

Experimental support for the transporter hypothesis of drug resistance in epilepsies has triggered efforts developing and validating approaches to overcome enhanced blood-brain barrier efflux transport. Testing in rodent models has rendered proof-of-concept for an add-on therapy with antiepileptic drugs. However, further development of the approach would require tolerability considerations as efflux transporters serve an important protective function throughout the body limiting distribution of harmful xenobiotics. Relevant progress has been made in the elucidation of mechanisms driving up-regulation of the multidrug transporter P-glycoprotein in response to seizure activity. Based on this knowledge, novel strategies have been evaluated targeting the signaling cascade that regulates P-glycoprotein in the epileptic brain. Further concepts might include by-passing blood-brain barrier transporters by intracerebral administration or by encapsulation of antiepileptic drugs in nano-sized carrier systems. It is important to note that the future perspectives of respective approaches are still questionable based on the limited evidence for a clinical relevance of transporter expression. Thus, techniques are urgently needed for non-invasive assessment of blood-brain barrier transporter function. Respective techniques would allow testing for a clinical correlation between pharmacosensitivity and transporter function, validating therapeutic strategies targeting efflux transporters and selecting patients with transporter over-expression for respective clinical trials. Provided that further clinical data render support for the transporter hypothesis, the main question remains whether patients exist in which transporter over-expression is the predominant mechanism of drug resistance and in which overcoming drug efflux is equivalent with overcoming drug resistance. Imaging techniques might provide a tool to address these questions in clinical epileptology. However, the complex pharmacological interactions between antiepileptic drugs, radiotracers, and transporter modulators used in these approaches as well as interindividual differences in the brain pathology might hamper clear-cut conclusions and limit the diagnostic significance.