Pharmacokinetics of orally administered low-dose rapamycin in healthy dogs

• Jeanne ^[1] ; Sara ^[2] ; Timothy ^[3] ; Chand ^[4] ; Paul ^[5] ; Ryan ^[6] ; Daniel ^[7] ; Alfred ^[8] ; Gina ^[9] ; Amy ^[10] ; Tomas ^[11]
  1. [1] C. Larson
  2. [2] D. Allstadt
  3. [3] M. Fan
  4. [4] Khanna
  5. [5] J. Lunghofer
  6. [6] J. Hansen
  7. [7] L. Gustafson
  8. [8] M. Legendre
  9. [9] D. Galyon
  10. [10] K. LeBlanc
  11. [11] Martin-Jimenez

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• Localización: American Journal of Veterinary Research, ISSN-e 1943-5681, ISSN 0002-9645, Vol. 77, Nº. 1, 2016, pág. 65
• Idioma: inglés
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  • Pharmacokinetics of orally administered low-dose rapamycin in healthy dogs Jeanne C. Larson, DVM; Sara D. Allstadt, DVM; Timothy M. Fan, DVM, PhD; Chand Khanna, DVM, PhD; Paul J. Lunghofer, MS; Ryan J. Hansen, PhD; Daniel L. Gustafson, PhD; Alfred M. Legendre, DVM; Gina D. Galyon, BS; Amy K. LeBlanc, DVM; Tomas Martin-Jimenez, DVM, PhD Departments of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996. (Larson, Allstadt, Legendre, Galyon, LeBlanc); Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana, IL 61801. (Fan); National Institute of Health, National Cancer Institute, Center for Cancer Research, Comparative Oncology Program, Bethesda, MD 20892. (Khanna); Flint Animal Cancer Center, Colorado State University, Fort Collins CO 80523. (Lunghofer, Hansen, Gustafson); Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996. (Martin-Jimenez) Drs. LeBlanc and Martin-Jimenez contributed equally to the study.

    Dr. LeBlanc's present address is National Institute of Health, National Cancer Institute, Center for Cancer Research, Comparative Oncology Program, Bethesda, MD 20892.

    Address correspondence to Dr. Larson (jeannelarsondvm@gmail.com).

    OBJECTIVE To determine the pharmacokinetics of orally administered rapamycin in healthy dogs.

    ANIMALS 5 healthy purpose-bred hounds.

    PROCEDURES 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 AND CLINICAL RELEVANCE 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.