title: Brain efflux index to investigate the influence of active efflux on brain distribution of pemetrexed and methotrexate.
abstract: Antifolates, in particular methotrexate (MTX), have been widely used in the treatment of primary and secondary tumors of the central nervous system (CNS). Pemetrexed (PMX) is a novel antifolate that also exhibits potent antitumor activity against CNS malignancies. Studies have shown that brain distribution of both antifolates is significantly restricted, possible due to active efflux transport at the blood-brain barrier (BBB). This study characterizes the brain-to-blood transport of PMX and MTX and examines the role of several efflux transporters in brain distribution of the antifolates by use of the intracerebral microinjection technique (brain efflux index). The results from this study show that both PMX and MTX undergo saturable efflux transport across the BBB, with elimination half-lives of approximately 39 minutes and 29 minutes, respectively. Of the various efflux transporters this study investigated, multidrug resistance-associated protein 2 (Mrp2) does not play an important role in the brain distribution of the two antifolate drugs. Interestingly, breast-cancer resistance protein (Bcrp) makes a significant contribution to the brain elimination of MTX but not PMX. In addition, the brain-to-blood transport of both antifolates was inhibited by probenecid and benzylpenicillin, suggesting the involvement of organic anion transporters in the efflux of these compounds from the brain, with organic anion transporter 3 (Oat3) being a possibility. Our results suggest that one of the underlying mechanisms behind the limited brain distribution of PMX and MTX is active efflux transport processes at the BBB, including a benzylpenicillin-sensitive transport system and/or the active transporter Bcrp.
authors.affiliation: Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Sagar
authors.initials: S
authors.lastname: Agarwal
authors.forename: William F
authors.initials: WF
authors.lastname: Elmquist
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000172:deficiency / Q000235:genetics; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D002199:Capillary Permeability / Q000187:drug effects; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005971:Glutamates / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D006207:Half-Life; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008845:Microinjections; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000172:deficiency / Q000235:genetics; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors / Q000378:metabolism; D000068437:Pemetrexed; D010400:Penicillin G / Q000494:pharmacology; D011339:Probenecid / Q000494:pharmacology
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D005493:Folic Acid Antagonists; D005971:Glutamates; D006147:Guanine; D008727:Methotrexate; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D029362:Organic Anion Transporters, Sodium-Independent; D000068437:Pemetrexed; D010400:Penicillin G; D011339:Probenecid; C501412:Abcg2 protein, mouse; C114338:organic anion transport protein 3