Article révisé par les pairs
Résumé : A number of drugs are largely metabolized after oral administration, especially by redox processes. Among the neuroleptics, loxapine, clotiapine and clozapine, which are seven-membered tricyclic molecules with a piperazine side-chain, are known to be extensively metabolized by oxidation. An electrochemical study of these compounds was initiated in order to determine their in vitro redox properties and to elucidate their oxidation mechanisms. The measurements were carried out in aqueous and non-aqueous media using voltammetric, cyclic voltammetric, coulometric, exhaustive electrolysis and thin-layer spectroelectrochemical techniques. The oxidation mechanisms, which differ essentially depending on the pH of the solution, are suggested. In view of these results, various similarities have been detected between the in vitro oxidation processes and the pharmacological behaviour reported in the literature. For example, the importance of the piperazine side-chain has been pointed out: oxidation no longer occurs if this side-chain is protonated; similarly, binding to the receptor is prevented if the lone electron pair of the tertiary atom is occupied. Nucleophilic additions have also been observed in non-aqueous media and the compounds have been identified using classical spectroscopic techniques. If the oxidation mechanism is identical on the piperazine chain for the three compounds, the process is somewhat different when it occurs on the tricyclic ring. Loxapine and clotiapine exhibit different behaviour from clozapine, in their electrochemical as well as in their pharmacological properties.