Disposition Pharmacokinetics and Metabolism of Aniracetam in Animals

This review summarises what is currently known of the preclinical pharmacokinetics of the cognition enhancer, aniracetam (Ro 13-5057). This drug combines 2 moieties, an anisoyl and a 2-pyrrolidinone group, which form a substituted imide structure. The metabolism of the drug has been thoroughly examined by use of several radiolabelled forms. The compound is rapidly cleaved to produce 3 primary metabolites: anisic acid, N-anisoyl-γ-aminobutyric acid and 2-pyrrolidinone. The latter compound undergoes extensive additional metabolism. Most of a radiolabelled dose is recovered in the urine with a small fraction appearing in the faeces and as CO₂ in expired air. The drug is totally metabolised, as the unchanged form is not recovered in excreted fluids. The parent compound is rapidly eliminated from the body and has a short half-life and large systemic clearance. Hepatic metabolism appears to account for most of the drug clearance; however, there may be contributions from the lung, vascular tissues and blood. One or more metabolites are lost more slowly than they are formed and one such compound appears to be succinimide. The gastrointestinal absorption of aniracetam is rapid and complete; however, only a very small fraction of the dose reaches the systemic circulation intact. The large apparent oral clearance is explained by presystemic elimination processes involving the liver, lung, and gastrointestinal tract and fluids. Aniracetam has a large apparent volume of distribution with only moderate binding to plasma proteins (approximately 66% bound). The drug traverses the placenta to produce measurable concentrations of intact drug in the fetus; however, most radioactivity found there is associated with metabolites. Aniracetam does not accumulate in the body with long term multiple administration but there is some accumulation of metabolites.