title: Discovery pharmacokinetic studies in mice using serial microsampling, dried blood spots and microbore LC-MS/MS.
abstract: BACKGROUND
  Initial pharmacokinetic (PK) studies of discovery compounds are conducted in mice to demonstrate exposure prior to conducting efficacy studies. PK information obtained from a single mouse by serial blood microsampling, dried blood spot collection and analyses using microbore (1 mm internal diameter column) LC-MS/MS is presented. Ex vivo blood to plasma concentration ratios (BPRs) from mouse PK studies were compared with in vitro BPRs for 15 compounds.
  
  
  RESULTS
  Two compounds were orally dosed and blood was collected at time points via serial blood sampling. The calculated PK parameters (AUC, T(max) and C(max)) were comparable across liquid blood, dried blood spot and plasma matrices. The BPR results from both methods were comparable.
  
  
  CONCLUSIONS
  Serial blood microsampling has led to reduced animal and compound usage with improved PK data. Ex vivo BPR is suitable in a discovery setting. Microbore LC-MS/MS is well suited in instances where sample volume is limited, and enables faster analyses, reduced solvent use, and less frequent MS source cleaning.
authors.affiliation: Department of Pharmacokinetics, Dynamics & Metabolism, Pfizer Global Research & Development, 10628 Science Center Drive, San Diego, CA 92121, USA. ravi.rahavendran@pfizer.com
authors.forename: Sadayappan V
authors.initials: SV
authors.lastname: Rahavendran
authors.forename: Sylvia
authors.initials: S
authors.lastname: Vekich
authors.forename: Heather
authors.initials: H
authors.lastname: Skor
authors.forename: Minerva
authors.initials: M
authors.lastname: Batugo
authors.forename: Leslie
authors.initials: L
authors.lastname: Nguyen
authors.forename: Bhasker
authors.initials: B
authors.lastname: Shetty
authors.forename: Zhongzhou
authors.initials: Z
authors.lastname: Shen
mesh_terms: D000818:Animals; D001800:Blood Specimen Collection; D002851:Chromatography, High Pressure Liquid; D000077547:Crizotinib; D059788:Dried Blood Spot Testing; D004353:Drug Evaluation, Preclinical; D007553:Isotope Labeling; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D004364:Pharmaceutical Preparations / Q000032:analysis* / Q000378:metabolism; D010599:Pharmacokinetics; D010879:Piperazines / Q000032:analysis / Q000378:metabolism; D010949:Plasma / Q000737:chemistry; D011720:Pyrazoles / Q000032:analysis / Q000378:metabolism; D011725:Pyridines / Q000032:analysis / Q000378:metabolism
chemical_list: D004364:Pharmaceutical Preparations; D010879:Piperazines; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C500026:palbociclib