SULFOXIDATION OF CHLORPROMAZINE AND THIORIDAZINE BY BOVINE LIVER - PREFERENTIAL METABOLIC PATHWAYS

The sulfoxidation of chlorpromazine (Thorazine), thioridazine (Mellaril), and some of their metabolites by a crude microsomal preparation from bovine liver was examined in an in vitro system which enables a rapid assessment of phenothiazine metabolism by various mammalian tissues. The enzymatic sulfoxidation of these drugs was found to require the presence of certain nicotinamide dinucleotide factors in their reduced form. Maximum activity was observed in the presence of NADPH. Preferential sulfoxidation pathways were found to differ between these two antipsychotic agents governing whether they are converted to pharmacologically active or inactive metabolites. Chlorpromazine under goes sulfoxidation to form its inactive ring-sulfoxide; in contrast, the sulfoxidation of thioridazine occurs preferentially at its side-chain sulfur residue to form mostly mesoridazine, a pharmacologically active metabolite. The ring-sulfur residue of thioridazine, unlike that of chlorpromazine, was very resistant toward this enzymatic process. In addition, various drugs including chloroquine and some of its analogues were tested for their ability to inhibit the formation of phenothiazine ring-sulfoxide. © 1979.