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Plasma pharmacokinetics and tissue and brain distribution of cisplatin in musk shrews

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Abstract

Purpose

Cisplatin induces nausea and emesis, even with antiemetic supportive care. To assess platinum exposure, which could activate nausea and emesis, we quantitated platinum in the brain and various organs, and hindbrain and spinal cord substance P, a key neuropeptide for the neuronal signaling of nausea and emesis.

Methods

Musk shrews, a model species for nausea and emesis research, were dosed intraperitoneally with 20 mg/kg cisplatin and euthanized at up to 72 h after injection. Concentrations of platinum were quantitated in plasma ultrafiltrate, plasma, lung, kidney, combined forebrain and midbrain, hindbrain, and spinal cord by flameless atomic absorption spectrometry. Hindbrains and spinal cords were analyzed for substance P by immunohistochemistry after injection of 20 or 30 mg/kg.

Results

Plasma ultrafilterable platinum concentrations decreased rapidly till 60 min after dosing and then more slowly by 24 h. The concentrations of total platinum in both the fore- and midbrain and the hindbrain were similar at all time points and were at least 20-fold lower than plasma total platinum concentrations. There were no significant changes in substance P immunoreactivity after cisplatin dosing. Histology revealed damage to the renal cortex by 72 h after injection of cisplatin.

Conclusions

This is the first study to examine platinum concentrations in musk shrews after administration of cisplatin and delineate substance P immunohistochemical staining in the hindbrain and spinal cord of this species. The platinum concentrations detected in the brain could potentially contribute to the neurological side effects of cisplatin, such as nausea and emesis.

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Acknowledgments

This study was supported in part by a pilot grant from the Women’s Cancer Research Center at the University of Pittsburgh Cancer Institute (UPCI) and Magee-Womens Cancer Research and Education Committee. Additional funding was supplied by the UPCI NIH Grant P30 CA047904 (Cancer Center Support Grant; CCSG), with core facility support to the Cancer Pharmacokinetic and Pharmacodynamic Facility (CPPF) and the Animal Facility (AF). We wish to thank the University of Pittsburgh, Division of Laboratory Animal Research, especially Dawn Everard, Katie Leschak, Megan Lambert, and Dr. Joseph Newsome for excellent care of the musk shrew colony at the UPCI.

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Authors and Affiliations

  1. Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    Julie L. Eiseman, Jan H. Beumer & Sandra Strychor

  2. Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA

    Jan H. Beumer

  3. Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Julie L. Eiseman

  4. Division of Laboratory Animal Resources, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA

    Lora H. Rigatti

  5. Biobehavioral Oncology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    Kelly Meyers, Samuel Dienel & Charles C. Horn

  6. Department of Neuroscience, School of Arts and Sciences, University of Pittsburgh, Pittsburgh, PA, USA

    Samuel Dienel

  7. Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Charles C. Horn

  8. Department of Anesthesiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Charles C. Horn

  9. Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA

    Charles C. Horn

  10. Hillman Cancer Center - Research Pavilion, G.17b, University of Pittsburgh, 5117 Centre Avenue, Pittsburgh, PA, 15213, USA

    Charles C. Horn

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  1. Julie L. Eiseman
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  2. Jan H. Beumer
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Correspondence to Charles C. Horn.

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Eiseman, J.L., Beumer, J.H., Rigatti, L.H. et al. Plasma pharmacokinetics and tissue and brain distribution of cisplatin in musk shrews. Cancer Chemother Pharmacol 75, 143–152 (2015). https://doi.org/10.1007/s00280-014-2623-5

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  • DOI: https://doi.org/10.1007/s00280-014-2623-5

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