A review of the pharmacokinetics, tolerability and pharmacodynamics of amisulpride in healthy volunteers

Abstract Amisulpride binds selectively to dopamine D 2 and D 3 receptors in the limbic system. Low doses of amisulpride preferentially block presynaptic D 2 /D 3 ‐dopamine autoreceptors, thereby enhancing dopaminergic transmission, whereas higher doses block postsynaptic receptors, thus inhibiting dopaminergic hyperactivity. Amisulpride is clinically effective on the negative symptoms of acute schizophrenia exacerbations at low dosages (50–300 mg/day), and also on the positive symptoms of the disease at high dosages (400–800 mg/day). Nineteen clinical studies involving 358 volunteers have investigated the pharmacokinetics, pharmacodynamics and tolerability of amisulpride. Amisulpride shows linear pharmacokinetics, a bioavailability of 48%, low protein binding (17%) and an elimination half‐life of ∼12 h. It is predominantly eliminated in the urine as the parent compound. It exhibits no significant detrimental effects in psychometric or memory tests up to the dose of 400 mg/day, inducing only mild impairment at high doses, whereas EEG data suggest an alertness‐enhancing effect at low doses (≤ 50 mg). Moreover, amisulpride does not potentiate the depressant effects on the central nervous system of alcohol and lorazepam. This tolerability profile is clearly better than that of haloperidol 4 mg/day and is consistent with a weak blocking effect on striatal D 2 receptors. In summary, studies in humans have shown that amisulpride is free of behavioural toxicity at doses exerting clear antipsychotic efficacy and confirm that its CNS effects may vary with the dose administered. Copyright © 2002 John Wiley & Sons, Ltd.