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Blood-Brain Barrier Active Efflux Transporters NeuroRx௡: The Journal of the American Society for Experimental NeuroTherapeutics Blood-Brain Barrier Active Efflux Transporters: ATP-Binding Cassette Gene Family Wolfgang Lo¨scher and Heidrun Potschka Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Hannover D-30559, Germany Summary: The blood-brain barrier (BBB) contributes to brain efflux transporters in the BBB include minimizing or avoiding homeostasis by protecting the brain from potentially harmful neurotoxic adverse effects of drugs that otherwise would pen- endogenous and exogenous substances. BBB active drug efflux etrate into the brain. However, ABC efflux transporters may transporters of the ATP-binding cassette (ABC) gene family also limit the central distribution of drugs that are beneficial to are increasingly recognized as important determinants of drug treat CNS diseases. Furthermore, neurological disorders such distribution to, and elimination from, the CNS. The ABC efflux as epilepsy may be associated with overexpression of ABC transporter P-glycoprotein (Pgp) has been demonstrated as a efflux transporters at the BBB, resulting in pharmacoresistance key element of the BBB that can actively transport a huge to therapeutic medication. Therefore, modulation of ABC ef- variety of lipophilic drugs out of the brain capillary endothelial flux transporters at the BBB forms a novel strategy to enhance cells that form the BBB. In addition to Pgp, other ABC efflux the penetration of drugs into the brain and may yield new transporters such as members of the multidrug resistance pro- therapeutic options for drug-resistant CNS diseases. Key tein (MRP) family and breast cancer resistance protein (BCRP) Words: P-glycoprotein, multidrug resistance proteins, epi- seem to contribute to BBB function. Consequences of ABC lepsy, antiepileptic drugs, depression, AIDS. INTRODUCTION pression of this efflux transporter in certain tissue com- partments such as the gastrointestinal tract and brain ATP-binding cassette (ABC) transporters are multido- capillary endothelial cells limits oral absorption and CNS main integral membrane proteins that use the energy of entry of many drugs.7 The use of Pgp-expressing cell ATP hydrolysis to translocate solutes across cellular lines, the generation of Pgp knockout mice as well as membranes in all mammalian species.1 ABC transporters studies using Pgp inhibitors in animals, contributed to a form one of the largest of all protein families and are better understanding on the role of active transport pro- central to many important biomedical phenomena, in- cesses for drug disposition.8 In addition to Pgp, the ABC cluding resistance of cancers and pathogenic microbes to transporters of the multidrug resistance protein (MRP; drugs.2 Elucidation of the structure and function of ABC ABCC) family and the breast cancer resistance protein transporters is essential to the rational design of agents to (BCRP; ABCG2) have a role in drug disposition.6,9 The control their function. family of mammalian ABC transporters, however, is far ABC transporters are increasingly recognized to be more extensive, and functionally highly diverse.1 In this important for drug disposition and response.3–7 P-glyco- review, we limit ourselves to the following ABC trans- protein (Pgp), the encoded product of the human multi- porters: Pgp, MRPs 1-6, and BCRP, i.e., ABC transport- drug resistance (MDR1) (ABCB1) gene, is of particular ers that are expressed at the blood-brain barrier (BBB) clinical relevance in that this transporter has a broad and, particularly Pgp, are involved in the regulation of substrate specificity, including a variety of structurally brain uptake and extrusion of drugs.6,7,9,10 divergent drugs in clinical use today.7–9 Moreover, ex- WHICH ABC TRANSPORTERS ARE Address correspondence and reprint requests to Dr. W. Lo¨scher, EXPRESSED AT THE BBB? Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, Foundation, Bu¨nteweg 17, D-30559 Drug uptake into the brain is dependent on a variety of Hannover, Germany. E-mail: [email protected]. factors, including the physical barrier presented by the 86 Vol. 2, 86–98, January 2005 © The American Society for Experimental NeuroTherapeutics, Inc. BLOOD-BRAIN BARRIER ABC TRANSPORTERS 87 TABLE 1. Substrates and Inhibitors of ABC Transporters that Are Expressed at the Blood-Brain Barrier ABC Transporter Substrates Inhibitors P-glycoprotein Anticancer drugs e.g., Doxorubicine, daunorubicine, 1st Generation e.g., verapamil, cyclosporin (ABCB1) vinblastine, vincristine, etoposide, teniposide, A, quinidine, quinine, amiodarone, de- paclitaxel, methotrexate tergents such as cremophore EL Immunosuppressive agents e.g., Cyclosporin A 2nd Generation e.g., PSC-833 (valspodar), GF120918 (elacridar), VX-710 (birico- dar), dexverapamil Corticoids e.g., Dexamethasone, hydrocortisone, 3rd Generation e.g., OC 144-093 (ONT- corticosterone, cortisol, aldosterone 093), LY335979 (zosuquidar), XR9576 (tariquidar), R101933 (laniquidar), GF120918 Analgesics e.g., Morphine HIV protease inhibitors e.g., Amprenavir, indinavir, saquinavir Cytokines e.g., IL-2, IL-4, IFN-␥ Antidiarrheal agents e.g., Loperamide Anthelminthic agents e.g., Ivermectin, abamectin Anti-gout agents e.g., Colchicines Histamine H2-receptor antagonists e.g., Cimetidine Calcium channel blocker e.g., verapamil Antiepileptic drugs e.g., Phenytoin, carbamazepine, lamotrigine, phenobarbital, felbamate, gabapentin, topiramate Antiemetics e.g., Domperidone, ondansetron Cardiac glycosides e.g., Digoxin Diagnostic (fluorescent) dyes e.g., Rhodamine-123 Antidepressants e.g., Amitryptiline, nortryptiline, doxepin, venlafaxine, paroxetine Antibiotics e.g., Erythromycin, valinomycin, tetra- cyclines, fluoroquinolines MRP1 (ABCC1) Anticancer drugs e.g., Etoposide, teniposide, vin- Sulfinpyrazone, probenecid, MK571, cristine, doxorubicine, daunorubicine, methotrex- LTC4, some Pgp inhibitors (e.g., cyclo- ate; Leukotriene C4 (LTC4), D4, E4; Various sporin A, verapamil, PSC 833) glutathione, glucuronide, and sulfate conjugates, but also unconjugated compounds (e.g., fluores- cein) MRP2 (ABCC2) Similar to MRP1 Similar to MRP1 MRP3 (ABCC3) Organic anion transporter with considerable overlap Classical organic anion transport inhibitors in drug substrates with MRP1 and MRP2 such as sulfinpyrazone, indomethacin, and probenecid MRP4 (ABCC4) Anticancer drugs such as methotrexate, 6-mercapto- purine, thioguanine MRP5 (ABCC5) cGMP, cAMP, 6-mercaptopurine, thioguanine, fluo- Probenecid and phosphodiesterase inhibi- rescein tors such as trequensin or sildenafil MRP6 (ABCC6) BQ-123 (an anionic cyclopentapeptide and endothe- lin receptor antagonist) BCRP (ABCG2) Several anticancer drugs; considerable overlap with GF120918 (inhibits also Pgp), fumitremor- Pgp, MRP1, and MRP2. Anthracyclines, mitox- gin C (FTC) and FTC analogues such as antrone, bisantrene, the camptothecins topotecan Ko132 and Ko134, CI1033 and SN-38, prazosin For reference see Schinkel and Jonker,6 Sun et al.,9 Gerk and Vore,11 and Fricker and Miller.14 BBB and the blood-CSF barrier (BCSFB) and the affin- into brain tissue. However, a very significant number of ity of the substrate for specific transport systems located lipid-soluble molecules, among them many useful ther- at both of these interfaces.11,12 It is the aggregate effect apeutic drugs have lower brain permeability than would of these factors that ultimately determines the total brain be predicted from a determination of their lipid solubil- exposure, and thus pharmacological efficacy, of a drug or ity. These molecules are substrates for the ABC efflux drug candidate. In general, the more lipid soluble a mol- transporters (Table 1) that are present in the BBB and ecule or drug is, the more readily it will tend to partition BCSFB, and the activity of these transporters very effi- NeuroRx௡, Vol. 2, No. 1, 2005 88 LO¨ SCHER AND POTSCHKA ciently removes the drug from the CNS, thus limiting tially harmful lipophilic compounds from natural sources brain uptake. and other lipophilic xenobiotics which otherwise could Pgp, a phosphorylated glycoprotein with an apparent penetrate the BBB by simple diffusion without any lim- molecular mass of 170 kDa, was the first of these ABC itation.10 The exact localization of Pgp in the BBB has transporters to be described, followed by the MRPs and been the object of numerous investigations using various more recently BCRP.9 All are expressed in the BBB or experimental approaches such as in situ hybridization BCSFB and combine to reduce the brain penetration of and immunohistochemistry.21 There are two types of many drugs. This phenomenon of multidrug resistance is human Pgp: type I (also termed “MDR1 Pgp”), encoded a major hurdle when it comes to the delivery of thera- by the MDR1 gene, which confers the drug resistance peutics to the brain, including brain cancer chemother- phenotype and drug efflux at the BBB (only this type will apy. Therefore, the development of strategies for bypass- dealt with in this review); and type II, encoded by ing the influence of these ABC transporters, for the MDR2, present in the canalicular membrane of hepato- design of effective drugs that are not substrates, and for cytes and functioning as a phosphatidylcholine translo- the development of inhibitors for the ABC transporters case.21 In rodents, the multidrug resistance type I Pgp is has become a high imperative for the pharmaceutical encoded by two genes (mdr1a, mdr1b).21 The substrate
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