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Plasma and cerebrospinal fluid pharmacokinetics of gemcitabine after intravenous administration in nonhuman primates.
- Source :
-
Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2001 May; Vol. 47 (5), pp. 411-4. - Publication Year :
- 2001
-
Abstract
- Purpose: Gemcitabine (dFdC) is a difluorine-substituted deoxycytidine analogue that has demonstrated antitumor activity against both leukemias and solid tumors. Pharmacokinetic studies of gemcitabine have been performed in both adults and children but to date there have been no detailed studies of its penetration into cerebrospinal fluid (CSF). The current study was performed in nonhuman primates to determine the plasma and CSF pharmacokinetics of gemcitabine and its inactive metabolite, difluorodeoxyuridine (dFdU) following i.v. administration.<br />Methods: Gemcitabine, 200 mg/kg, was administered i.v. over 45 min to four nonhuman primates. Serial plasma and CSF samples were obtained prior to, during, and after completion of the infusion for determination of gemcitabine and dFdU concentrations. Gemcitabine and dFdU concentrations were measured using high-performance liquid chromatography (HPLC) and modeled with model-dependent and model-independent methods.<br />Results: Plasma elimination was rapid with a mean t1/2 of 8 +/- 4 min (mean +/- SD) for gemcitabine and 83 +/- 8 min for dFdU. Gemcitabine total body clearance (ClTB) was 177 +/- 40 ml/min per kg and the Vdss was 5.5 +/- 1.0 l/kg. The maximum concentrations (Cmax) and areas under the time concentration curves (AUC) for gemcitabine and dFdU in plasma were 194 +/- 64 microM and 63.8 +/- 14.6 microM.h, and 783 +/- 99 microM and 1725 +/- 186 microM.h, respectively. The peak CSF concentrations of gemcitabine and dFdU were 2.5 +/- 1.4 microM and 32 +/- 41 microM, respectively. The mean CSF:plasma ratio was 6.7% for gemcitabine and 23.8% for dFdU.<br />Conclusions: There is only modest penetration of gemcitabine into the CSF after i.v. administration. The relatively low CSF exposure to gemcitabine after i.v. administration suggests that systemic administration of this agent is not optimal for the treatment of overt leptomeningeal disease. However, the clinical spectrum of antitumor activity and lack of neurotoxicity after systemic administration of gemcitabine make this agent an excellent candidate for further studies to assess the safety and feasibility of intrathecal administration.
- Subjects :
- Animals
Antimetabolites, Antineoplastic administration & dosage
Antimetabolites, Antineoplastic blood
Antimetabolites, Antineoplastic cerebrospinal fluid
Area Under Curve
Chromatography, High Pressure Liquid
Deoxycytidine administration & dosage
Deoxycytidine analogs & derivatives
Deoxycytidine blood
Deoxycytidine cerebrospinal fluid
Infusions, Intravenous
Macaca mulatta
Male
Gemcitabine
Antimetabolites, Antineoplastic pharmacokinetics
Deoxycytidine pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 0344-5704
- Volume :
- 47
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Cancer chemotherapy and pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 11391856
- Full Text :
- https://doi.org/10.1007/s002800000253