Plasma pharmacokinetics and tissue and brain distribution of cisplatin in musk shrews.
OBJECTIVE
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.
Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
Julie L
JL
Eiseman
Jan H
JH
Beumer
Lora H
LH
Rigatti
Sandra
S
Strychor
Kelly
K
Meyers
Samuel
S
Dienel
Charles C
CC
Horn
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000378:metabolism / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004639:Emetics / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009325:Nausea / Q000097:blood / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010984:Platinum / Q000097:blood / Q000378:metabolism; D012788:Shrews; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013373:Substance P / Q000378:metabolism; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D004639:Emetics; D013373:Substance P; D010984:Platinum; D002945:Cisplatin