Implications of ATP-binding cassette transporters for brain pharmacotherapies.
By preventing pharmacological compounds from achieving therapeutic levels in tissue, ATP-binding cassette (ABC) transporters complicate new drug discoveries. This has profound implications for pharmacotherapies, which go far beyond the need to deliver higher drug dosages. Comparative studies have recently shown that the expression and functionality of efflux proteins vary strongly both between species and strains, and in response to pathophysiological stimuli. This shatters hopes that it might become possible to predict drug biodistribution across species barriers. From this perspective, there is a need for more precise empirical biodistribution experiments to be performed in preparation for clinical trials. In such studies, the accumulation and elimination of drugs should be tested in various species under conditions resembling, as closely as possible, those in which a drug is clinically planned to be used. This approach should markedly enhance the overall success of new drugs and foster progress in neurological therapies.
Hermann
Dirk M
DM
Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, CH-8091 Zurich, Switzerland. dirk.hermann@usz.ch
Bassetti
Claudio L
CL
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism; D010599:Pharmacokinetics; D014018:Tissue Distribution
D018528:ATP-Binding Cassette Transporters; D004364:Pharmaceutical Preparations