Journal
PHARMACOLOGY & THERAPEUTICS
Volume 123, Issue 1, Pages 80-104Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pharmthera.2009.03.017
Keywords
Blood-brain barrier; Blood-cerebrospinal fluid barrier; Drug interactions; P-glycoprotein; ABC transporters; In vitro-in vivo correlations
Categories
Funding
- NIA NIH HHS [AG 031485, R33 AG031485, R33 AG031485-02] Funding Source: Medline
- NICHD NIH HHS [P50 HD044404-01, P50 HD044404] Funding Source: Medline
- NIGMS NIH HHS [R01 GM054447, P01 GM032165, R01 GM054447-16, P01 GM032165-210011, GM 32165] Funding Source: Medline
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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. (C) 2009 Elsevier Inc. All rights reserved.
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