Research Articles Drug Development

Archives of Pharmacal Research

, Volume 34, Issue 11, pp 1983-1988

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

  • Young G. ShinAffiliated withDepartment of Drug Metabolism and Pharmacokinetics, GenentechDepartment of Drug Metabolism and Pharmacokinetics, Genentech Email author 
  • , Teresa DongAffiliated withDepartment of Drug Metabolism and Pharmacokinetics, Genentech
  • , Bilin ChouAffiliated withDepartment of Drug Metabolism and Pharmacokinetics, Genentech
  • , Kapil MenghrajaniAffiliated withDepartment of Drug Metabolism and Pharmacokinetics, Genentech

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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.

Key words

Matrix-assisted laser desoprtion/ionization (MALDI) Quantitation Loperamide Tissue analysis ESI-LC-MS/MS Mdr1a/1b(−/−)