Stereoselective pharmacokinetic analysis and antiepileptic activity of N-2-hydroxypropyl valpromide, a central nervous system--active chiral valproylamide.

The purpose of this study was to evaluate the anticonvulsant activity and pharmacokinetics (PK) of a novel chiral CNS-active 2-hydroxypropyl valpromide (HP-VPD), a derivative of valproic acid (VPA). The individual enantiomers, R, S, and racemic (R,S)-HP-VPD were synthesized and evaluated for their pharmacokinetics and pharmacodynamics in a stereoselective manner. A stereoselective gas chromatography (GC) assay for simultaneous quantification of HP-VPD enantiomers in plasma and urine was developed and used to investigate the pharmacokinetics of HP-VPD in dogs. Pharmacodynamic analysis in rats showed that (S)-HP-VPD was 2.5 times more potent as an anticonvulsant in the maximal electroshock seizure (MES) test than its enantiomer and approximately 10 times more potent than VPA. No significant differences were observed in major PK parameters (clearance, volume of distribution, and half-life) between S and (R)-HP-VPD, and this suggested that pharmacodynamic differences could be attributed to the intrinsic pharmacodynamics of each enantiomer rather than to a preferable pharmacokinetic profile. The pharmacokinetic (metabolic) analysis showed that the fraction metabolized to HP-VPD-glucuronide ranged from 5% to 7% and no biotransformation of HP-VPD to VPA and 2-ketopropyl valpromide was observed. This is the first report of significant stereoselectivity in the anticonvulsant activity of a valproylamide with a chiral carbon situated on the alkyl chain of the amine moiety.

Stereoselective pharmacokinetic analysis of valnoctamide, a CNS-active chiral amide analogue of valproic acid, in dogs, rats, and mice.

The purpose of this study was to evaluate the stereoselective pharmacokinetics of valnoctamide (VCD) in dogs, rats, and mice; which are the most common animal models for pharmacokinetic, pharmacologic, and toxicologic evaluation; and to compare it with previously published human data. Racemic VCD (mixture of four stereoisomers) was administered intravenously to six mongrel dogs and to rats (five rats per time-point), and intraperitoneally to mice (five mice per time-point). Plasma concentrations of the individual stereoisomers were measured by a stereospecific gas chromatography assay. In dogs, (2S,3R)-VCD had a larger clearance (0.33 L/h x kg) and a larger volume of distribution (0.79 L/kg) than its two diastereomers (0.24-0.25 L/h x kg and 0.65 L/kg, respectively). A tendency toward slightly higher clearance and volume of distribution values for (2S,3R)-VCD was observed in rats and mice as well. Consequently, in all three animal species the half-life (t1/2) of (2S,3R)-VCD was not different from the t1/2 of the other three VCD stereoisomers. The stereoselective pharmacokinetics of VCD as observed in dogs, rats, and mice is in line with the stereoselectivity previously observed in healthy subjects and epileptic patients.

The structural requirements for the design of antiepileptic-glycine derivatives.

Glycine is a major inhibitory neurotransmitter and recent reports have shown that certain lipophilic derivatives of glycine demonstrate anticonvulsant activity in intact animals. In these studies, glycinamide derivatives were found to be more potent than their corresponding glycine analogues. Consequently, the objective of the current study was to investigate the pharmacokinetics and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following phenyl derivatives of glycinamide: N'-benzyl glycinamide, N-benzyloxycarbonyl glycinamide (Z-glycinamide), Z-glycine, N-Z,N'-benzyl glycinamide and N-phenylacetyl glycinamide. The antiepileptic activity and neurotoxicity was carried out in classical animal models for antiepileptic screening. The pharmacokinetics of the active compounds were studied in dogs, a common animal model for comparative crossover pharmacokinetic studies. Of the compounds investigated in this study, Z-glycinamide, N'-benzyl glycinamide and N-Z,N'-benzyl glycinamide were found to be active. Therefore, the disposition of Z-glycinamide and N-Z,N'-benzyl glycinamide in comparison to Z-glycine was studied in plasma, brain, liver and urine of rats. The disposition of Z-glycinamide and N-Z,N'-benzyl glycinamide into the brain was better than that of Z-glycine. Unlike glycine or glycinamide, Z-glycinamide and N-Z,N'-benzyl glycinamide showed antiepileptic activity in animal models due to their better pharmacodynamic and pharmacokinetic properties. The pharmacokinetics of Z-glycinamide was similar in dogs and rats. Substitution of the Z group with the analogous phenylacetyl moiety led to inactive compounds. In an analogous series of compounds, the loss of the anticonvulsant activity may be due to pharmacodynamic and pharmacokinetic reasons. This study provides certain clues concerning the structural requirements for the design of antiepileptic-active glycine derivatives.

Disposition of two tetramethylcyclopropane analogues of valpromide in the brain, liver, plasma and urine of rats.

2,2,3,3-Tetramethylcyclopropane carboxamide (TMCD) and N-methyl TMCD (M-TMCD) are analogues of valpromide (VPD) or amide derivatives of valproic acid (VPA), one of the major antiepileptic drugs (AEDs). In rodent models both TMCD and M-TMCD are more potent as anticonvulsants than VPA. The present study investigates the pharmacokinetics (PK) of TMCD and M-TMCD in rats by monitoring the levels of these two amides in the brain, liver, plasma and urine of rats. The disposition of TMCD and M-TMCD was analyzed in a comparative manner with that of VPD and VPA, previously studied by us. The following similar PK parameters were obtained for TMCD and M-TMCD, respectively: clearance, 5 and 5.6 ml/min/kg; volume of distribution (Vss), 0.72 and 0.96 l/kg; half-life (t1/2), 1.1 and 1. 2 h; and mean residence time (MRT), 2.41 and 2.8 h. The ratio of AUCs of TMCD of liver to plasma and brain to plasma were 1.67 and 1. 13, respectively. The ratios of the AUCs of M-TMCD of liver to plasma and brain to plasma were 1.43 and 0.99, respectively. Thus, both compounds distribute evenly between plasma and brain, but their distribution into the liver is 50% larger than that in the plasma. Therefore, PK analysis of TMCD and M-TMCD brain levels gave major PK parameters similar to those obtained from the plasma data. The fraction metabolized of M-TMCD to TMCD was 32%. The brain was not found to be a metabolic site for the M-TMCD to TMCD biotransformation which occurred primarily in the liver as indicated by the high liver concentrations of TMCD as a metabolite of M-TMCD. Unlike VPD, TMCD and M-TMCD did not undergo amide-acid biotransformation to their corresponding inactive acid, 2,2,3, 3-tetramethylcyclopropane carboxylic acid (TMCA). Both M-TMCD and TMCD distribute better into the brain than VPA, a fact that may contribute to their better anticonvulsant activity.

The disposition of valproyl glycinamide and valproyl glycine in rats.

PURPOSE: To investigate the disposition of valproyl glycinamide and valproyl glycine in rats and to compare it with that of valproic acid (VPA) and valpromide which were studied previously. METHODS: The study was carried out by monitoring the brain and liver levels of valproyl glycinamide and valproyl glycine (as a function of time after iv dosing) in addition to the regular pharmacokinetic (PK) monitoring of plasma and urine levels of these compounds. RESULTS: The following PK parameters were obtained for valproyl glycinamide and valproyl glycine, respectively: clearance, 7.1 and 16 ml/ min/kg; volume of distribution (Vss), 0.78 and 0.41 l/kg; half-life, 1.1 and 0.37 h; and mean residence time, 1.8 and 0.4 h. The ratios of AUCs of valproyl glycinamide of liver to plasma and brain to plasma were 0.70 and 0.66, respectively. The ratios of the AUCs of valproyl glycine of liver to plasma and brain to plasma were 0.19 and 0.02, respectively. CONCLUSIONS: Valproyl glycinamide distributes better in the brain than VPA, a fact which may contribute to its better anticonvulsant activity. Valproyl glycine was barely distributed in the brain, a fact which may explain its lack of anticonvulsant activity. In addition to the liver, the brain was found to be a minor metabolic site of the biotransformation of valproyl glycinamide to valproyl glycine.

Disposition of valpromide, valproic acid, and valnoctamide in the brain, liver, plasma, and urine of rats.

Valpromide (VPD) and valnoctamide (VCD) are amide derivatives of valproic acid (VPA), one of the major antiepileptic drugs (AEDs). In rodent models, both VPD and VCD are more potent as anticonvulsants than VPA. However, in humans, VPD served as a prodrug to VPA, whereas VCD acts as a drug on its own, which is not biotransformed to its corresponding acid--valnoctic acid (VCA). The present study investigates the pharmacokinetics (PKs of VPD and VCD in rats by monitoring the levels of these two amide isomers in the brain, liver, plasma, and urine of rats. The disposition of VPD and VCD was analyzed in a comparative manner with that of VPA. The following PK parameters were obtained for VPD and VCD, respectively: clearance, 6.1 and 3 ml/min/kg; volume of distribution (Vss), 0.63 and 0.58 liter/kg; half-life (t1/2), 42 and 94 min; and mean residence time (MRT), 102 and 196 min. The clearance of VCD in rats was half of that of VPD, and their Vss was similar. Therefore, VCD, t1/2, and MRT were twice as long as those of VPD.PK analysis of VPD and VCD liver and brain levels gave similar major PK parameters to those obtained from the plasma data. VPD underwent hepatic biotransformation to VPA, which persisted in the liver and brain for a longer period than VPD. The fraction metabolized of VPD to VPA was 42%. The brain was not found to be a metabolic site of the VPD-VPA biotransformation. Unlike VPD, VCD did not undergo amid-acid biotransformation to its corresponding acid, but was eliminated by biotransformation to unidentified metabolites. In contrast to VPD and VCD that distributed about evenly between the plasma, liver, and brain, VPA showed different disposition patterns in the plasma, liver, and brain. VCD and VPD distribute better into the brain than VPA, a fact that may contribute to their better anticonvulsant activity.