title: Plasma protein binding limits the blood brain barrier permeation of the pyrethroid insecticide, deltamethrin.
abstract: Previous pharmacokinetic studies of deltamethrin (DLM) have revealed that brain levels of this highly lipophilic pyrethroid insecticide are only 15-20% of plasma levels. Experiments were performed to assess determinants limiting CNS access including plasma protein binding and the efflux transporter, P-gp. A human brain microvascular endothelial cell line, hCMEC/D3, was utilized as a model in vitro system to evaluate blood-brain barrier (BBB) permeation. Incubation of DLM with a series of human serum albumin (HSA) concentrations showed that unbound (fu) DLM ranged from 80% with 0.01% HSA to ∼20% at the physiologically-relevant 4% HSA. A positive correlation (R=0.987) was seen between fu and cellular uptake. Concentration-dependent uptake of DLM in 0.01% HSA was non-linear and was reduced at 4°C and by the P-gp inhibitor cyclosporine (CSA), indicative of a specific transport process. Cellular accumulation of [(3)H]-paclitaxel, a P-glycoprotein (P-gp) substrate, was increased by CSA but not by DLM, suggesting that DLM is neither a substrate nor an inhibitor of P-gp. The concentration-dependent uptake of DLM from 4% HSA was linear and not significantly impacted by temperature or CSA. In situ brain perfusion studies monitoring brain association of DLM at 0.01% and 4% HSA confirmed the aforementioned in vitro findings. This study demonstrates that brain uptake of DLM under normal physiological conditions appears to be a passive, non-saturable process, limited by the high protein binding of the pyrethroid.
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, 250 west Green St. Athens, GA, 30602, United States.
authors.forename: Manoj
authors.initials: M
authors.lastname: Amaraneni
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, 250 west Green St. Athens, GA, 30602, United States.
authors.forename: Anshika
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, 250 west Green St. Athens, GA, 30602, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Pang
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, 250 west Green St. Athens, GA, 30602, United States.
authors.forename: Srinivasa
authors.initials: S
authors.lastname: Muralidhara
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, 250 west Green St. Athens, GA, 30602, United States.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Cummings
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, 250 west Green St. Athens, GA, 30602, United States.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: White
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, 250 west Green St. Athens, GA, 30602, United States.
authors.forename: James V
authors.initials: JV
authors.lastname: Bruckner
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, 250 west Green St. Athens, GA, 30602, United States. Electronic address: jzastre@uga.edu.
authors.forename: Jason
authors.initials: J
authors.lastname: Zastre
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002199:Capillary Permeability; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007306:Insecticides / Q000378:metabolism*; D007700:Kinetics; D016014:Linear Models; D008297:Male; D008954:Models, Biological; D009570:Nitriles / Q000378:metabolism*; D010477:Perfusion; D011485:Protein Binding; D011722:Pyrethrins / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D012709:Serum Albumin / Q000378:metabolism*; D000075462:Serum Albumin, Human; D013696:Temperature
chemical_list: C422455:ALB protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D007306:Insecticides; D009570:Nitriles; D011722:Pyrethrins; D012709:Serum Albumin; C017180:decamethrin; D000075462:Serum Albumin, Human
keywords: Blood-Brain barrier; Insecticide; P-glycoprotein; Pyrethroid; Transport