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

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.

Pharmacokinetics and tissue distribution of novel platinum containing anticancer agent BP‐C1 studied in rabbits using sector field inductively coupled plasma mass spectrometry

“…Organs of primary platinum accumulation were kidneys, liver, spleen and muscular tissue near the injection site (Table ). Low platinum concentration in the brain indicated slight transport of BP‐C1 through the blood‐brain‐barrier, which is in concordance with the data established for other platinum‐containing agents, for example cisplatin, carboplatin and oxaliplatin as well as for platinum metal complexes in general . Although animal sample was small (three animals per dosage form), some tendencies for platinum elimination from the organs could be demonstrated.…”

Estimation of body surface area in the musk shrew (Suncus murinus): a small animal for testing chemotherapy-induced emesis

“…A cisplatin dosage of approximately >70 mg/m 2 is highly emetogenic in humans 15 but the equivalent dose in musk shrews (female, 7.0; male, 7.7 mg/kg) does not produce emesis. Ultrafilterable platinum clearance in our previous shrew pharmacokinetic study, normalized to BSA utilizing K m is 341 mL/min/m 2 , which is similar to that value reported in humans of 397 mL/min/m 2 (assuming a 70 kg, 1.73 m 2 human) 16, 17 , suggesting there may be a susceptibility difference between humans and shrews.…”

Changes in cognitive functions and cerebral grey matter and their associations with inflammatory markers, endocrine markers, and APOE genotypes in testicular cancer patients undergoing treatment

“…So far, it has been assumed that cisplatin does not permeate the blood-brain-barrier (BBB) and thus the neurotoxic effects of BEP in the brain were considered to be minimal (Gregg et al 1992). However, recent evidence suggests that cisplatin is in fact able to cross the blood-brain-barrier (Eiseman et al 2014), and although the amount crossing may be small, neural populations including progenitor cells, oligodendrocytes, and hippocampal neurons are exceptionally vulnerable to even small concentrations with possible adverse effects on cognition (Andres et al 2014;Dietrich et al 2006;Gong et al 2011;Rzeski et al 2004).…”