title: Determination of loperamide in mdr1a/1b knock-out mouse brain tissue using matrix-assisted laser desorption/ionization mass spectrometry and comparison with quantitative electrospray-triple quadrupole mass spectrometry analysis.
abstract: Recently matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) imaging has been used to analyze small molecule pharmaceutical compounds directly on tissue sections to determine spatial distribution within target tissue and organs. The data presented to date usually indicate relative amounts of drug within the tissue. The determination of absolute amounts is still done using tissue homogenization followed by traditional liquid chromatography-tandem mass spectrometry (LC-MS/MS). In this study, the quantitative determination of loperamide, an antidiarrheal agent and a P-glycoprotein substrate, in mdr1a/1b (-/-) mouse brain tissue sections using MALDI MS on a quadrupole time-of-flight mass spectrometry is described. 5 mg/mL α-cyano-4-hydroxycinnamic acid in 50% acetonitrile with 0.1% trifluoroacetic acid and 0.5 μM reserpine was used as the MALDI matrix. The calibration curve constructed by the peak intensities of standard samples from MALDI MS was linear from 0.025 to 0.5 μM with r² = 0.9989. The accuracy of calibration curve standards was 78.3-105.9% and the percent deviation was less than 25%. Comparison between direct MALDI tissue analysis and conventional tissue analysis using homogenization followed by electrospray LC-MS/MS was also explored.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, CA 94080, USA. yshin@gene.com
authors.forename: Young G
authors.initials: YG
authors.lastname: Shin
authors.forename: Teresa
authors.initials: T
authors.lastname: Dong
authors.forename: Bilin
authors.initials: B
authors.lastname: Chou
authors.forename: Kapil
authors.initials: K
authors.lastname: Menghrajani
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000930:Antidiarrheals / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism*; D002138:Calibration; D055808:Drug Discovery / Q000379:methods; D015507:Drugs, Investigational / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D057230:Limit of Detection; D008139:Loperamide / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D051379:Mice; D018345:Mice, Knockout; D008832:Microchemistry / Q000295:instrumentation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D059906:Neuroimaging / Q000379:methods*; D015203:Reproducibility of Results; D021241:Spectrometry, Mass, Electrospray Ionization; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014018:Tissue Distribution; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000930:Antidiarrheals; D015507:Drugs, Investigational; D008139:Loperamide; D009419:Nerve Tissue Proteins; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3