N-desmethyl-loperamide is selective for P-glycoprotein among three ATP-binding cassette transporters at the blood-brain barrier.
[(11)C]N-desmethyl-Loperamide ([(11)C]dLop) is used in positron emission tomography (PET) to measure the in vivo activity of efflux transporters that block the passage of drugs across the blood-brain barrier. The three most prevalent ATP-binding cassette efflux transporters at the blood-brain barrier are P-glycoprotein (P-gp), multidrug resistance protein 1 (Mrp1), and breast cancer resistance protein (BCRP). We sought to measure the selectivity of dLop among these three transporters. The selectivity of dLop at low concentrations (< or =1 nM) was measured both as the accumulation of [(3)H]dLop in human cells that overexpress each transporter and as the uptake of [(11)C]dLop in brains of mice that lack genes encoding P-gp, Mrp1, or BCRP. The selectivity of dLop at high concentrations (> or =20 microM) was measured as the inhibition of uptake of a fluorescent substrate and the change in cytotoxicity of drugs effluxed at each transporter. Accumulation of [(3)H]dLop was lowest in cells overexpressing P-gp, and the uptake of [(11)C]dLop was highest in brains of mice lacking P-gp. At high concentrations, dLop selectively inhibited P-gp function and also decreased the resistance of only the P-gp-expressing cells to cytotoxic agents. dLop is selective for P-gp among these three transporters, but its activity is dependent on concentration. At low concentrations (< or =1 nM), dLop acts only as a substrate; at high concentrations (> or =20 microM), it acts as both a substrate and an inhibitor (i.e., a competitive substrate). Because low concentrations of radiotracer are used for PET imaging, [(11)C]dLop acts selectively and only as a substrate for P-gp.
Kannan
Pavitra
P
Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA.
Brimacombe
Kyle R
KR
Zoghbi
Sami S
SS
Liow
Jeih-San
JS
Morse
Cheryl
C
Taku
Andrew K
AK
Pike
Victor W
VW
Halldin
Christer
C
Innis
Robert B
RB
Gottesman
Michael M
MM
Hall
Matthew D
MD
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000493:pharmacokinetics; D001692:Biological Transport / Q000502:physiology*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002560:Cerebrovascular Circulation; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D008139:Loperamide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D051379:Mice; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D014018:Tissue Distribution / Q000502:physiology; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D019380:Anti-HIV Agents; D006023:Glycoproteins; D008139:Loperamide; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D019275:Radiopharmaceuticals; C419149:N-demethylloperamide