Plasma and cerebrospinal fluid pharmacokinetics of intravenous oxaliplatin, cisplatin, and carboplatin in nonhuman primates.
OBJECTIVE
Describe and compare the central nervous system pharmacology of the platinum analogues, cisplatin, carboplatin, and oxaliplatin and develop a pharmacokinetic model to distinguish the disposition of active drug from inert platinum species.


METHODS
Oxaliplatin (7 or 5 mg/kg), cisplatin (2 mg/kg), or carboplatin (10 mg/kg) was given i.v. Serial plasma and cerebrospinal fluid (CSF) samples were collected over 24 hours. Plasma ultrafiltrates were prepared immediately. Platinum concentrations were measured using atomic absorption spectrometry. Areas under the concentration x time curve were derived using the linear trapezoidal method. CSF penetration was defined as the CSF AUC(0-24)/plasma ultrafiltrate AUC(0-24) ratio. A four-compartment model with first-order rate constants was fit to the data to distinguish active drug from inactive metabolites.


RESULTS
The mean +/- SD AUCs in plasma ultrafiltrate for oxaliplatin, cisplatin, and carboplatin were 61 +/- 22, 18 +/- 6, and 211 +/- 64 micromol/L hour, respectively. The AUCs in CSF were 1.2 +/- 0.4 micromol/L hour for oxaliplatin, 0.56 +/- 0.08 micromol/L hour for cisplatin, and 8 +/- 2.2 mumol/L hour for carboplatin, and CSF penetration was 2.0%, 3.6%, and 3.8%, respectively. For oxaliplatin, cisplatin, and carboplatin, the pharmacokinetic model estimated that active drug accounted for 29%, 79%, and 81% of platinum in plasma ultrafiltrate, respectively, and 25%, 89%, and 56% of platinum in CSF, respectively. The CSF penetration of active drug was 1.6% for oxaliplatin, 3.7% for cisplatin, and 2.6% for carboplatin.


CONCLUSIONS
The CSF penetration of the platinum analogues is limited. The pharmacokinetic model distinguished between active drug and their inactive (inert) metabolites in plasma and CSF.
Jacobs
Shana S
SS
Pharmacology and Experimental Therapeutics Section, Pediatric Oncology Branch, National Cancer Institute, 10 Center Drive, Bethesda, MD 20815, USA. Jacobss@mail.nih.gov
Fox
Elizabeth
E
Dennie
Christopher
C
Morgan
Lindsey B
LB
McCully
Cynthia L
CL
Balis
Frank M
FM
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D019540:Area Under Curve; D016190:Carboplatin / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D002945:Cisplatin / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D007262:Infusions, Intravenous; D008253:Macaca mulatta; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D009944:Organoplatinum Compounds / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D000077150:Oxaliplatin
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D016190:Carboplatin; D002945:Cisplatin