title: Increased permeability-glycoprotein inhibition at the human blood-brain barrier can be safely achieved by performing PET during peak plasma concentrations of tariquidar.
abstract: The permeability-glycoprotein (P-gp) efflux transporter is densely expressed at the blood-brain barrier, and its resultant spare capacity requires substantial blockade to increase the uptake of avid substrates, blunting the ability of investigators to measure clinically meaningful alterations in P-gp function. This study, conducted in humans, examined 2 P-gp inhibitors (tariquidar, a known inhibitor, and disulfiram, a putative inhibitor) and 2 routes of administration (intravenous and oral) to maximally increase brain uptake of the avid and selective P-gp substrate (11)C-N-desmethyl-loperamide (dLop) while avoiding side effects associated with high doses of tariquidar.
  
  
  METHODS
  Forty-two (11)C-dLop PET scans were obtained from 37 healthy volunteers. PET was performed with (11)C-dLop under the following 5 conditions: injected under baseline conditions without P-gp inhibition, injected 1 h after intravenous tariquidar infusion, injected during intravenous tariquidar infusion, injected after oral tariquidar, and injected after disulfiram. (11)C-dLop uptake was quantified with kinetic modeling using metabolite-corrected arterial input function or by measuring the area under the time-activity curve in the brain from 10 to 30 min.
  
  
  RESULTS
  Neither oral tariquidar nor oral disulfiram increased brain uptake of (11)C-dLop. Injecting (11)C-dLop during tariquidar infusion, when plasma tariquidar concentrations reach their peak, resulted in a brain uptake of the radioligand approximately 5-fold greater than baseline. Brain uptake was similar with 2 and 4 mg of intravenous tariquidar per kilogram; however, the lower dose was better tolerated. Injecting (11)C-dLop after tariquidar infusion also increased brain uptake, though higher doses (up to 6 mg/kg) were required. Brain uptake of (11)C-dLop increased fairly linearly with increasing plasma tariquidar concentrations, but we are uncertain whether maximal uptake was achieved.
  
  
  CONCLUSIONS
  We sought to increase the dynamic range of P-gp function measured after blockade. Performing (11)C-dLop PET during peak plasma concentrations of tariquidar, achieved with concurrent administration of intravenous tariquidar, resulted in greater P-gp inhibition at the human blood-brain barrier than delayed administration and allowed the use of a lower, more tolerable dose of tariquidar. On the basis of prior monkey studies, we suspect that plasma concentrations of tariquidar did not fully block P-gp; however, higher doses of tariquidar would likely be associated with unacceptable side effects.
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland; and Taub Institute, Columbia University Medical Center, New York, New York wck2107@cumc.columbia.edu.
authors.forename: William C
authors.initials: WC
authors.lastname: Kreisl
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland; and.
authors.forename: Ritwik
authors.initials: R
authors.lastname: Bhatia
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland; and.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Morse
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland; and.
authors.forename: Alicia E
authors.initials: AE
authors.lastname: Woock
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland; and.
authors.forename: Sami S
authors.initials: SS
authors.lastname: Zoghbi
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland; and.
authors.forename: H Umesha
authors.initials: HU
authors.lastname: Shetty
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland; and.
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland; and.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Innis
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D061605:Administration, Intravenous; D000284:Administration, Oral; D000328:Adult; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008139:Loperamide / Q000031:analogs & derivatives; D008297:Male; D010539:Permeability; D049268:Positron-Emission Tomography; D011804:Quinolines / Q000009:adverse effects / Q000097:blood* / Q000378:metabolism / Q000494:pharmacology*; D012449:Safety
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011804:Quinolines; C419149:N-demethylloperamide; D008139:Loperamide; C402343:tariquidar
keywords: N-desmethyl-loperamide; P-glycoprotein (P-gp); positron emission tomography (PET); tariquidar