title: Pharmacokinetics of orally administered low-dose rapamycin in healthy dogs.
abstract: OBJECTIVE
  To determine the pharmacokinetics of orally administered rapamycin in healthy dogs.
  
  
  METHODS
  5 healthy purpose-bred hounds.
  
  
  METHODS
  The study consisted of 2 experiments. In experiment 1, each dog received rapamycin (0.1 mg/kg, PO) once; blood samples were obtained immediately before and at 0.5, 1, 2, 4, 6, 12, 24, 48, and 72 hours after administration. In experiment 2, each dog received rapamycin (0.1 mg/kg, PO) once daily for 5 days; blood samples were obtained immediately before and at 3, 6, 24, 27, 30, 48, 51, 54, 72, 75, 78, 96, 96.5, 97, 98, 100, 102, 108, 120, 144, and 168 hours after the first dose. Blood rapamycin concentration was determined by a validated liquid chromatography-tandem mass spectrometry assay. Pharmacokinetic parameters were determined by compartmental and noncompartmental analyses.
  
  
  RESULTS
  Mean ± SD blood rapamycin terminal half-life, area under the concentration-time curve from 0 to 48 hours after dosing, and maximum concentration were 38.7 ± 12.7 h, 140 ± 23.9 ng•h/mL, and 8.39 ± 1.73 ng/mL, respectively, for experiment 1, and 99.5 ± 89.5 h, 126 ± 27.1 ng•h/mL, and 5.49 ± 1.99 ng/mL, respectively, for experiment 2. Pharmacokinetic parameters for rapamycin after administration of 5 daily doses differed significantly from those after administration of 1 dose.
  
  
  CONCLUSIONS
  Results indicated that oral administration of low-dose (0.1 mg/kg) rapamycin to healthy dogs achieved blood concentrations measured in nanograms per milliliter. The optimal dose and administration frequency of rapamcyin required to achieve therapeutic effects in tumor-bearing dogs, as well as toxicity after chronic dosing, need to be determined.
authors.forename: Jeanne C
authors.initials: JC
authors.lastname: Larson
authors.forename: Sara D
authors.initials: SD
authors.lastname: Allstadt
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Fan
authors.forename: Chand
authors.initials: C
authors.lastname: Khanna
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lunghofer
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Hansen
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Gustafson
authors.forename: Alfred M
authors.initials: AM
authors.lastname: Legendre
authors.forename: Gina D
authors.initials: GD
authors.lastname: Galyon
authors.forename: Amy K
authors.initials: AK
authors.lastname: LeBlanc
authors.forename: Tomas
authors.initials: T
authors.lastname: Martin-Jimenez
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D002853:Chromatography, Liquid / Q000379:methods; D004285:Dogs / Q000097:blood*; D006207:Half-Life; D020123:Sirolimus / Q000493:pharmacokinetics*
chemical_list: D020123:Sirolimus