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

Abstract

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. Milacemide dose‐dependently increased CSF glycine and glycinamide (intermediary metabolite) concentrations. This confirms that milacemide is a CNS glycine prodrug. 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. Tmax and t1/2 were significantly increased and Cmax 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 Cmax and AUC values. 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 Cmax 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. 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. 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.

Comparison of serum, cerebrospinal fluid and brain extracellular fluid pharmacokinetics of lamotrigine

“…In order to study CSF pharmacokinetics, direct sampling of CSF with simultaneous serum sampling has been successfully used ( Patsalos et al ., 1992 ; Semba et al ., 1993 ; Lolin et al ., 1994 ; Walker et al ., 1998 ; Doheny et al ., 1999 ; Nagaki et al ., 1999 ). The limited accessibility of CSF and the impracticability of repeated sampling in humans have meant that most of these drug studies have been carried out in animal models.…”

Progress in Drug Delivery to the Central Nervous System by the Prodrug Approach

“…Milacemide (2- n -pentylaminoacetamide) is considered to be a glycine prodrug. It was demonstrated that it readily crosses the BBB and its N -dealkylation by monoamine oxidase type B releases glycinamide, which is converted into glycine [ 37 ]. Yu et al [ 38 ] have recently shown that 2-propyl-1-aminopentane and 2-propylpentylglycinamide are readily deaminated by monoamine oxidase B and by semicarbazide-sensitive amine oxidase.…”

The new generation of anti-epileptic drugs

“…Milacemide (CP-1552S), a glycine pro-drug (glycine is an inhibitory neurotransmitter in the CNS), had minimal efficacy in patients with epilepsy even though it possessed anticonvulsant activity in animal models. A lack of understanding of the pharmacokinetic characteristics of milacemide may have been responsible for its demise [25].…”