Antiepileptic drug pharmacokinetics and neuropharmacokinetics in individual rats by repetitive withdrawal of blood and cerebrospinal fluid: milacemide

Content Provider	Scilit
Author	Semba, Jun'ichi Curzon, Gerald Curzon Patsalos, Philip N.
Copyright Year	1993
Description	Journal: British Journal of Pharmacology 1 The kinetics and metabolism of milacemide have been studied in an animal model which allows the simultaneous investigation of the temporal inter-relationships of drugs and metabolites in blood (pharmacokinetics) and cerebrospinal fluid (CSF, neuropharmacokinetics) in individual freely moving rats. 2 Milacemide dose-dependently increased CSF glycine and glycinamide (intermediary metabolite) concentrations. This confirms that milacemide is a CNS glycine prodrug. 3 Pretreatment with l-deprenyl (2 mg $kg^{−1}$), a specific inhibitor of monoamine oxidase type B (MAO-B), almost completely prevented the formation of glycinamide and increased milacemide accumulation in CSF. $T_{max}$ and $t_{1/2}$ were significantly increased and $C_{max}$ and AUC values were decreased for glycinamide compared to controls. Pretreatment with clorgyline (5 mg $kg^{−1}$), a specific inhibitor of MAO-type A, only moderately decreased glycinamide $C_{max}$ and AUC values. 4 After milacemide administration (100, 200 and 400 mg $kg^{−1}$, i.p.) serum and CSF milacemide concentrations rose linearly and dose-dependently. Serum glycinamide concentrations exhibited small dose-dependent rises but these were not linearly related. In contrast, CSF glycinamide concentrations rose linearly and dose-dependently with $C_{max}$ values 2.5, 3.2 and 4.1 times greater than the corresponding values for serum glycinamide after giving 100, 200 and 400 mg $kg^{−1}$ respectively of milacemide. 5 Serum glycine concentrations were unaffected but CSF concentrations increased dose-dependently and these were significant at the higher milacemide doses (200 and 400 mg $kg^{−1}$). Animals given 400 mg $kg^{−1}$ milacemide had glycine values which were still significantly elevated 7 h later. 6 In conclusion, serum milacemide rapidly enters and equilibrates with the CNS compartment where it is metabolised primarily by MAO-B to glycinamide and finally to glycine. Metabolism in the peripheral compartment is negligible.
Related Links	http://europepmc.org/articles/pmc1908144?pdf=render https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1908144/pdf https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.1993.tb13514.x
Ending Page	1124
Page Count	8
Starting Page	1117
e-ISSN	14765381
DOI	10.1111/j.1476-5381.1993.tb13514.x
Journal	British Journal of Pharmacology
Issue Number	4
Volume Number	108
Language	English
Publisher	Wiley-Blackwell
Publisher Date	1993-04-01
Access Restriction	Open
Subject Keyword	Journal: British Journal of Pharmacology Cerebrospinal Fluid Neuropharmacokinetics Monoamine Oxidase
Content Type	Text
Resource Type	Article