Extracellular fluid concentrations of cisplatin, carboplatin, and oxaliplatin in brain, muscle, and blood measured using microdialysis in nonhuman primates.
OBJECTIVE
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, AUC(0-4h) for microdialysis sampling from the vein was similar to standard plasma UF sampling. The median AUC(0-4h) 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 (AUC(0-4h), 0.4-0.9 microM h) were substantially lower than brain ECF concentrations (AUC(0-4h), 2.0-8.6 microM 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.
Jacobs
Shana
S
Pediatric Oncology Branch, NCI, National Institutes of Health, Bldg. 10 CRC/Rm. 1-5750, 10 Center Drive, Bethesda, MD 20892, USA.
McCully
Cynthia L
CL
Murphy
Robert F
RF
Bacher
John
J
Balis
Frank M
FM
Fox
Elizabeth
E
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D016190:Carboplatin / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D002945:Cisplatin / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D045604:Extracellular Fluid / Q000378:metabolism*; D008253:Macaca mulatta; D008297:Male; D017551:Microdialysis / Q000379:methods; D009132:Muscles / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D000077150:Oxaliplatin; D014462:Ultrafiltration
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D016190:Carboplatin; D002945:Cisplatin