Pharmacokinetics of pramiracetam in normal volunteers and in animals

Introduction

Pramiracetam (Figure 1) belongs to the class of organic compounds known as alpha amino acids and derivatives. These are amino acids in which the amino group is attached to the carbon atom immediately adjacent to the carboxylate group (alpha carbon), or a derivative thereof. Pramiracetam (CI-879) is a new nootropic agent, belonging to the 'acetam' family,proposed for use in age-related memory disturbances. The drug was found, in previous studies, to be potentially effective in scopolamine-induced amnesia in animals. Moreover pramiracetam has a protective effects in rats greater than piracetam and oxiracetam. The improvement of memory has been related to the action of the drug on acetylcholine neurotransmission and the HACU system in rat brain (increase of choline captation in the hippocampus). Pramiracetam has been previously approved in some eastern European countries under the brand names Pramistar, Neupramir, and Remen. It was also previously approved in the United States with orphan drug designation . Pramiracetam has been studied for the use in Alzheimer's disease and as an adjunct treatment to restore cognitive functioning post-electroconvulsive therapy in severe depression.[1]

Pramiracetam effects on scopolamine-inducedamnesia in healthy volunteers

Pramiracetam has been evaluated for its potential antiamnesic properties in scopolamine-induced amnesia in healthy volunteers. Two groups of twelve males, 18-42 and 55-65 years old, respectively, were randomly assigned to oral treatment with pramiracetam (600 mg twice a day) or with placebo for 10 consecutive days. On day 11 each subject was injected intramuscularly with scopolamine hydrobromide (0.5 mg). Before scopolamine injection and then 1, 3 and 6 h after it, subjects were administered the following psychometric tests: simple and choice visual reaction times, digit symbol substitution test, Rey's 15 words test for short and long term verbal memory. Scopolamine significantly impaired episodic memory and selective attention tests in both scopolamine and placebo groups. Instead visuo-motor and incidental learning measures were unaffected. Pramiracetam, when compared to placebo, was able to partially reduce the amnesic effects induced by scopolamine both in young and old subjects.[1]

Pharmacokinetics of oral pramiracetam in normal volunteers

The pharmacokinetics of pramiracetam, a new, investigational, cognition activator, were assessed in normal male volunteers as part of a clinical tolerance study. In a double-blind, randomized design, two groups of six subjects each received alternating placebo and single 400, 800, 1,200, and 1,600 mg oral doses of pramiracetam after an overnight fast. Mean±SD peak plasma concentrations of the four dose groups (2.71±0.54, 5.40± 1.34, 6.13±0.71, 8.98±0.71 μg/mL) were attained between two to three hours following drug administration. The harmonic mean elimination half-life (4.5-6.5hours), the mean total body clearance (4.45-4.85mL/min/kg), the mean renal clearance (1.83-3.00 mL/min/kg), and the mean apparent volume of distribution (1.82-2.94L/kg) were independent of dose, whereas the peak plasma concentrations and area under the curves increased as a linear function of dose. No significant side effects were observed at any dose level.

The pharmacokinetics of pramiracetam could be described by bi- or tri-exponential equations corresponding to the one-compartment or two-compartment body model. The terminal elimination half-life showed considerable variation among subjects. This variation was not related to the increasing dose. The total body clearance remained remarkably constant,showing <10% fluctuation over the dose range. The clearance values are relatively small compared to the hepatic blood flow, suggesting that little or no first-pass metabolism will occur provided that the drug is not metabolized in the gut, The magnitude of the apparent volume of distribution indicates that pramiracetam is widely distributed in tissues, since the estimated values far exceed total body water volume.Tissue distribution in rats showed that 14C-labeledpramiracetam partitioned extensively into highly per-fused organs, and the tissue radioactivity concentrations were ten to 100 times greater than those inplasmas.[2]

Pharmacokinetics of pramiracetam in animals

Pharmacokinetic rules of pramiracetam were studied here. After giving pramiracetam orally to dogs, Fang et al. drew their blood at various times. The drug concentrations in blood plasma were detected by HPLC. 3p87 program was used to calculate the pharmacokinetic parameters. The time-concentration curve corresponded to one apartment model. T1/2 was about 2.3-3.9 hours in various doses. After pramiracetam was given to rats per os, high concentrations of pramiracetam were detected in the rats' tissues. The kidney had the highest concentration of pramiracetam; the liver had the next highest concentration, and then the intestine, lung, muscle, heart, gonad, spleen and sebum had the high concentration in order. The drug was also detected in the brain. 0.7% of the given dose was excreted in unchanged form in bile in 24 hours. 28.26% and 6.35% were excreted in urine and feces respectively in 72 hours. The plasma protein combining rate detected by the method of balance dialysis was 20.1-22.2%.[3]

References

1.Mauri M, Sinforiani E, Reverberi F, Merlo P, Bono G. Pramiracetam effects on scopolamine-induced amnesia in healthy volunteers. Arch Gerontol Geriatr. 1994;18(2):133-139. doi:10.1016/0167-4943(94)00542-7

2.Chang T, Young RM, Goulet JR, Yakatan GJ. Pharmacokinetics of oral pramiracetam in normal volunteers. J Clin Pharmacol. 1985;25(4):291-295. doi:10.1002/j.1552-4604.1985.tb02841.x

3.Fang Z, Liu X, Xiao Y, Jiang W. Hua Xi Yi Ke Da Xue Xue Bao. 1999;30(4):411-413. 

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