Abstract
Purpose
Valproic acid (VPA), a widely used antiepileptic, also inhibits histone deacetylase (HDAC), and is undergoing evaluation as an anti-cancer agent. We studied the pharmacokinetics of VPA in the plasma and cerebrospinal fluid (CSF) in a non-human primate model that is highly predictive of human CSF penetration to determine if levels of VPA required to inhibit HDAC in in vivo models can be attained.
Methods
Oral VPA, 75 mg/kg, was administered to four non-human primates. Serial samples of blood (n = 4) and CSF (n = 3) were obtained for pharmacokinetic studies of total and free VPA. Plasma and CSF VPA concentrations were measured using the commercially available Abbott AxSYM VPA assay reagent system (Abbott Laboratories, Abbott Park, IL, USA). The resultant plasma and CSF data were evaluated using pharmacokinetic modeling methods.
Results
At a dose of 75 mg/kg, the maximum plasma concentration of VPA was 130.1 ± 70.6 μg/ml (mean ± standard deviation) for total drug and 53.3 ± 44.4 μg/ml for free drug. The mean plasma area under the curve (AUC) for total drug was 680 ± 233 μg/ml h and for free drug 146 ± 89 μg/ml hr. The maximum CSF concentration occurred 2–3 h after administration and was 28.2 ± 18.6 μg/ml. The CSF AUC for VPA was 108 ± 52 μg/ml h. The CSF penetration of VPA was 12.9 ± 5.1% for total drug and 57.0 ± 8.7% for free drug. Disappearance from the plasma followed non-linear kinetics with a V max of 321.2 ± 65.6 μg/kg/min and a K m of 17.2 ± 13.7 mg/l.
Conclusion
Valproic acid deserves further study for the treatment of CNS tumors given its high CSF penetration after oral dosing coupled with the anti-tumor activity observed in preclinical studies.
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References
Blaney SM, Balis FM, Hegedus L, Heideman RL, McCully C, Murphy RF, Kelley JA, Poplack DG (1990) Pharmacokinetics and metabolism of cyclopentenyl cytosine in nonhuman primates. Cancer Res 50:7915–7919
Lundberg B, Nergardh A, Boreus LO (1982) Plasma concentrations of valproate during maintenance therapy in epileptic children. J Neurol 228:133–141
Sztajnkrycer MD (2002) Valproic acid toxicity: overview and management. J Toxicol Clin Toxicol 40:789–801
Lindberger M, Tomson T, Wallstedt L, Stahle L (2001) Distribution of valproate to subdural cerebrospinal fluid, subcutaneous extracellular fluid, and plasma in humans: a microdialysis study. Epilepsia 42:256–261
Li XN, Shu Q, Su JM, Perlaky L, Blaney SM, Lau CC (2005) Valproic acid induces growth arrest, apoptosis, and senescence in medulloblastomas by increasing histone hyperacetylation and regulating expression of p21Cip1, CDK4, and CMYC. Mol Cancer Ther 4:1912–1922
Council NR (1996) Guide for the care and use of laboratory animals. National Academy Press, Washington DC
D’Argenio DSA (1997) ADAPT II User’s Guide: pharmacokinetic/pharmacodynamic systems analysis software. Biomedical Simulations Resource, University of Southern California, Los Angeles
Wong H, Rurak DW, Kumar S, Kwan E, Abbott FS, Riggs KW (2001) Dose-dependent pharmacokinetics and metabolism of valproic acid in newborn lambs and adult sheep. Drug Metab Dispos 29:664–675
Loscher W (1999) Valproate: a reappraisal of its pharmacodynamic properties and mechanisms of action. Prog Neurobiol 58:31–59
Muraszko K, Sung C, Walbridge S, Greenfield L, Dedrick RL, Oldfield EH, Youle RJ (1993) Pharmacokinetics and toxicology of immunotoxins administered into the subarachnoid space in nonhuman primates and rodents. Cancer Res 53:3752–3757
Koch-Weser J, Sellers EM (1976) Binding of drugs to serum albumin (first of two parts). N Engl J Med 294:311–316
Mellett LB (1977) Physicochemical considerations and pharmacokinetic behavior in delivery of drugs to the central nervous system. Cancer Treat Rep 61:527–531
Panomvana Na Ayudhya D, Suwanmanee J, Visudtibhan A (2006) Pharmacokinetic parameters of total and unbound valproic acid and their relationships to seizure control in epileptic children. Am J Ther 13:211–217
Rapeport WG, Mendelow AD, French G, MacPherson P, Teasdale E, Agnew E, Thompson GG, Brodie MJ (1983) Plasma protein-binding and CSF concentrations of valproic acid in man following acute oral dosing. Br J Clin Pharmacol 16:365–369
Witt O, Schweigerer L, Driever PH, Wolff J, Pekrun A (2004) Valproic acid treatment of glioblastoma multiforme in a child. Pediatr Blood Cancer 43:181
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Stapleton, S.L., Thompson, P.A., Ou, CN. et al. Plasma and cerebrospinal fluid pharmacokinetics of valproic acid after oral administration in non-human primates. Cancer Chemother Pharmacol 61, 647–652 (2008). https://doi.org/10.1007/s00280-007-0519-3
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DOI: https://doi.org/10.1007/s00280-007-0519-3