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Pharmacokinetics and cerebrospinal fluid penetration of phenylacetate and phenylbutyrate in the nonhuman primate.
- Source :
-
Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2001 May; Vol. 47 (5), pp. 385-90. - Publication Year :
- 2001
-
Abstract
- Introduction: Phenylbutyrate (PB) and its metabolite phenylacetate (PA) demonstrate anticancer activity in vitro through promotion of cell differentiation, induction of apoptosis through the p21 pathway, inhibition of histone deacetylase, and in the case of PB, direct cytotoxicity. We studied the pharmacokinetics, metabolism, and cerebrospinal fluid (CSF) penetration of PA and PB after intravenous (i.v.) administration in the nonhuman primate.<br />Methods: Three animals received 85 mg/kg PA and 130 mg/kg PB as a 30-min infusion. Blood and CSF samples were obtained at 15, 30, 35, 45, 60 or 75 min, and at 1.5, 2.5, 3.5, 5.5, 6.5, 8.5, 10.5 and 24.5 h after the start of the infusion. Plasma was separated immediately, and plasma and CSF were frozen until HPLC analysis was performed.<br />Results: After i.v. PA administration, the plasma area under the concentration-time curve (AUC) of PA (median +/- SD) was 82 +/- 16 mg/ml.min, the CSF AUC was 24 +/- 7 mg/ml.min, clearance (Cl) was 1 +/- 0.3 ml/min per kg, and the AUCCSF:AUCplasma ratio was 28 +/- 19%. After i.v. PB administration, the plasma PB AUC was 19 +/- 3 mg/ml.min, the CSF PB AUC was 8 +/- 11 mg/ml.min, the PB Cl was 7 +/- 1 ml/min per kg, and the AUCCSF:AUCplasma ratio was 41 +/- 47%. The PA plasma AUC after i.v. PB administration was 50 +/- 9 mg/ml.min, the CSF AUC was 31 +/- 24 mg/ml.min, and the AUCCSF:AUCplasma ratio was 53 +/- 46%.<br />Conclusions: These data indicate that PA and PB penetrate well into the CSF after i.v. administration. There may be an advantage to administration of PB over PA, since the administration of PB results in significant exposure to both active compounds. Clinical trials to evaluate the activity of PA and PB in pediatric central nervous system tumors are in progress.
- Subjects :
- Animals
Antimetabolites, Antineoplastic administration & dosage
Antimetabolites, Antineoplastic blood
Antimetabolites, Antineoplastic cerebrospinal fluid
Antimetabolites, Antineoplastic therapeutic use
Area Under Curve
Central Nervous System Neoplasms drug therapy
Chromatography, High Pressure Liquid
Infusions, Intravenous
Macaca mulatta
Male
Phenylacetates administration & dosage
Phenylacetates blood
Phenylacetates cerebrospinal fluid
Phenylacetates therapeutic use
Phenylbutyrates administration & dosage
Phenylbutyrates blood
Phenylbutyrates cerebrospinal fluid
Phenylbutyrates therapeutic use
Antimetabolites, Antineoplastic pharmacokinetics
Phenylacetates pharmacokinetics
Phenylbutyrates 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 :
- 11391852
- Full Text :
- https://doi.org/10.1007/s002800000256