title: P-glycoprotein is a factor in the uptake of dextromethorphan, but not of melperone, into the mouse brain: evidence for an overlap in substrate specificity between P-gp and CYP2D6.
abstract: In this study, the role of P-glycoprotein (P-gp) for the pharmacokinetics of dextromethorphan, a CYP2D6 substrate, and of melperone, a CYP2D6 inhibitor, was investigated. The substances were administered subcutaneously near the nape of the neck of wild-type mice and of abcb1ab (-/-) mice. One hour after injection, concentrations of the two drugs in cerebrum, plasma and in different organs were measured by high-performance liquid chromatography. No significant differences between wild-type mice and abcb1ab (-/-) mice were observed for melperone, suggesting that P-gp is not involved in the uptake of melperone into the brain or other organs of mice. The concentration of dextromethorphan in the brain was more than twice as high in abcb1ab (-/-) mice compared to wild-type mice. Therefore, P-gp appears to be a factor in the uptake of dextromethorphan into the mouse brain, and abcb1-polymorphisms need to be considered for CYP2D6 phenotyping experiments with this drug. There is an overlap in substrate specificity between P-gp and CYP2D6. P-gp is a factor in the uptake of dextromethorphan, but not of melperone.
authors.affiliation: Max Planck Institute for Psychiatry, 80804 Munich, Germany. uhr@mpipsykl.mpg.de
authors.forename: Manfred
authors.initials: M
authors.lastname: Uhr
authors.forename: Christian
authors.initials: C
authors.lastname: Namendorf
authors.forename: Markus T
authors.initials: MT
authors.lastname: Grauer
authors.forename: Markus
authors.initials: M
authors.lastname: Rosenhagen
authors.forename: Martin
authors.initials: M
authors.lastname: Ebinger
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D002090:Butyrophenones / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D003915:Dextromethorphan / Q000378:metabolism*; D007668:Kidney / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D013154:Spleen / Q000201:enzymology / Q000378:metabolism; D013379:Substrate Specificity; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002090:Butyrophenones; D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6; C008522:metylperon