Determination of a novel carbamate AChE inhibitor meserine in mouse plasma, brain and rat plasma by LC-MS/MS: application to pharmacokinetic study after intravenous and subcutaneous administration

J Pharm Biomed Anal. 2014 Aug 5:96:156-61. doi: 10.1016/j.jpba.2014.03.025. Epub 2014 Mar 26.

Abstract

In this paper a simple and sensitive method for determination of a novel phenylcarbamate AChE inhibitor, meserine, in mouse plasma, brain and rat plasma was evaluated using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Separation was achieved on an Alltech Alltima-C18 column (150mm×2.1mm, 3μm, Deerfield, IL, USA) with isocratic elution at a flow rate of 0.35ml/min. Detection was performed under the multiple reaction monitoring (MRM) mode using an electrospray ionization (ESI) in the positive ion mode. The protein precipitation and liquid-liquid extraction methods were used for the pretreatment of plasma and brain homogenates, respectively. The calibration curves of meserine showed good linearity over the concentration range of 0.5-1000ng/ml for mouse and rat plasma and 0.5-500ng/ml for mouse brain. The intra- and inter-day precision were less than 9.34% and the accuracy was from 95.34% to 107.78% for QC samples. The validated method was successfully applied to a preclinical pharmacokinetic study of meserine in mice and rats after intravenous and subcutaneous administration. The results showed that this novel drug could easily cross the blood-brain barrier to reach the site of drug action. Meserine was rapidly absorbed with a high subcutaneous absolute bioavailability (>90%).

Keywords: Carbamate AChE inhibitor; LC–MS/MS; Meserine; Pharmacokinetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intravenous
  • Animals
  • Biological Availability
  • Blood-Brain Barrier / metabolism
  • Brain / metabolism
  • Cholinesterase Inhibitors / administration & dosage
  • Cholinesterase Inhibitors / pharmacokinetics*
  • Chromatography, High Pressure Liquid / methods*
  • Humans
  • Injections, Subcutaneous
  • Liquid-Liquid Extraction
  • Male
  • Meptazinol / administration & dosage
  • Meptazinol / analogs & derivatives*
  • Meptazinol / pharmacokinetics
  • Mice
  • Phenylcarbamates / administration & dosage
  • Phenylcarbamates / pharmacokinetics*
  • Rats
  • Rats, Sprague-Dawley
  • Reproducibility of Results
  • Sensitivity and Specificity
  • Spectrometry, Mass, Electrospray Ionization / methods
  • Tandem Mass Spectrometry / methods*
  • Tissue Distribution

Substances

  • Cholinesterase Inhibitors
  • Phenylcarbamates
  • meserine
  • Meptazinol