Asenapine review, part I: chemistry, receptor affinity profile, pharmacokinetics and metabolism

Asenapine is a second-generation (atypical) antipsychotic currently marketed for the treatment of schizophrenia and bipolar mania/mixed episodes.

The purpose of this review is to describe the chemistry, pharmacodynamics, and pharmacokinetics of asenapine.

Asenapine has a complex pharmacodynamic profile with affinities at multiple dopamine, serotonin, histamine, and α-adrenergic receptors, all at which asenapine functions as an antagonist. Sublingual asenapine tablets are absorbed in the oral mucosa, with a Tmax occurring between 30 and 90 min. Terminal half-life is approximately 24 h. Asenapine has multiple inactive metabolites, produced via direct glucuronidation (primarily via UGT1A4), demethylation, and oxidative metabolism (primarily via CYP1A2). Hepatic and renal routes contribute approximately equally to the elimination of asenapine and its metabolites. Two notable drug-drug interactions are evident: asenapine (an inhibitor of CYP2D6) can increase plasma levels of paroxetine, and fluvoxamine (a CYP1A2 inhibitor) can increase plasma levels of asenapine. Caution is required when coadministering asenapine with drugs that are both substrates and inhibitors of CYP2D6.