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Extracellular fluid concentrations of cisplatin, carboplatin, and oxaliplatin in brain, muscle, and blood measured using microdialysis in nonhuman primates

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Abstract

Purpose

Cisplatin, carboplatin, and oxaliplatin are chemically reactive anticancer drugs with modest activity in brain tumors. Previously, we have demonstrated that drug exposure in cerebrospinal fluid (CSF) for these platinum analogs is <5% of the plasma ultrafiltrate (UF) drug exposure in nonhuman primates. Microdialysis is a minimally invasive in vivo method for sampling small molecules in the blood and tissue extracellular fluid (ECF). The purpose of this study was to estimate the penetration of platinum analogs into the brain ECF.

Methods

We measured free concentrations of cisplatin, carboplatin, and oxaliplatin in ECF of brain, muscle, and blood of nonhuman primates using microdialysis and compared ECF platinum concentrations in blood and brain to plasma UF and CSF concentrations obtained using conventional sampling methods.

Results

For all three platinum analogs, AUC0-4h for microdialysis sampling from the vein was similar to standard plasma UF sampling. The median AUC0-4h ratio for vein to plasma UF was 1.1 (range, 0.9–1.4). The platinum analogs had limited distribution (<5%) to the CSF and brain ECF. CSF penetration predicts for the limited penetration of the platinum analogs into brain ECF, but concordance between CSF and brain ECF measurements was poor. CSF oxaliplatin concentrations (AUC0-4h, 0.4–0.9 μM h) were substantially lower than brain ECF concentrations (AUC0-4h, 2.0–8.6 μM h).

Conclusions

The penetration of platinum analogs into CSF and brain is limited. The differences in the CNS penetrations among the three platinum analogs are not clinically significant. For cisplatin and carboplatin, CSF penetration appears to be a surrogate for brain extracellular free drug exposure.

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Acknowledgment

This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

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Authors and Affiliations

  1. Pediatric Oncology Branch, NCI, National Institutes of Health, Bldg. 10 CRC/Rm. 1-5750, 10 Center Drive, Bethesda, MD, 20892, USA

    Shana Jacobs, Cynthia L. McCully, Robert F. Murphy, Frank M. Balis & Elizabeth Fox

  2. Division of Veterinary Resources, ORS, NIH, Bethesda, MD, USA

    John Bacher

  3. Department of Hematology/Oncology, Children’s National Medical Center, Washington, DC, USA

    Shana Jacobs

Authors
  1. Shana Jacobs
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  2. Cynthia L. McCully
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  3. Robert F. Murphy
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  4. John Bacher
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  5. Frank M. Balis
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  6. Elizabeth Fox
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Corresponding author

Correspondence to Elizabeth Fox.

Additional information

Shana Jacobs and Cynthia L. McCully have contributed equally to this work.

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Jacobs, S., McCully, C.L., Murphy, R.F. et al. Extracellular fluid concentrations of cisplatin, carboplatin, and oxaliplatin in brain, muscle, and blood measured using microdialysis in nonhuman primates. Cancer Chemother Pharmacol 65, 817–824 (2010). https://doi.org/10.1007/s00280-009-1085-7

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  • DOI: https://doi.org/10.1007/s00280-009-1085-7

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