Pharmacokinetics of Oxiracetam

Oxiracetam is a structural analogue of piracetam. This compound has enhancing effects on vigilance and memory. In comparison with piracetam, oxiracetam exhibits greater improvement in memory and has been used extensively for the treatment of dementia, including AD, VaD, MID , and mixed forms. Green et al. (1992) failed to demonstrate a diference from placebo in AD patients. In contrast, Maina et al. (1989) studied 289 patients with MID in a double-blind placebo- controlled trial and after 12 weeks of treatment found that oxiracetam reduced behavioural symptoms.

Chemistry

Oxiracetam, or (RS)-2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetamide, is a synthetic compound of the racetam family. Racetams share a pyrrolidine nucleus, a five member nitrogenous ring with a ketone bonded oxygen at R2. This 2-pyrrolidone ring is bound to the terminal carbon of an acetamide group, an ethyl amide chain with a ketone bond (C=O) at the alpha carbon.Oxiracetam is substituted with an additional hydroxy group at R4, which is a chiral center for the molecule.Oxiracetam is presumably produced as a racemate of its enantiomers. Oxiracetam is structurally analogous to piracetam, which lacks the R4 hydroxy substitution of oxiracetam.

Pharmacokinetics

Oxiracetam is well absorbed from the gastrointestinal tract with a bioavailability of 56-82%.Peak serum levels are reached within one to three hours after a single 800 mg or 2000 mg oral dose, with the maximal serum concentration reaching between 19-31 μg/ml at these doses.

Oxiracetam is mainly cleared renally and approximately 84% is excreted unchanged in the urine. The half-life of oxiracetam in healthy individuals is about 8 hours, whereas it is 10–68 hours in patients with renal impairment. There is some penetration of the blood–brain barrier with brain concentrations reaching 5.3% of those in the blood (measured one hour after a single 2000 mg intravenous dose).

Clearance rates range from 9 to 95 ml/min and steady-state concentrations when 800 mg is given twice daily range from 60 μM to 530 μM.

The highest brain concentrations of oxiracetam are found in the septum pellucidum, followed by the hippocampus, the cerebral cortex and with the lowest concentrations in the striatum after a 200 mg/kg oral dose given to rats.Oxiracetam may be quantitated in plasma, serum or urine by liquid chromatography with one of several different detection techniques.

The major metabolites of Oxiracetam include: beta-hydroxy-2-pyrrolidone, N-aminoacetyl-GABOB, GABOB (beta-hydroxy-GABA) and glycine.Thus its metabolic route is exactly parallel to that of piracetam, aniracetam, phenylpiracetam, and all other members of the -racetam family, and also pyroglutamic acid.