In general, these classes of drugs are rapidly absorbed from the GI tract (Table 13.1), but there is considerable individual patient variation in peak plasma concentrations.83 Chlorpromazine has been the most widely studied phenothi-azine, and it is believed that thioxanthenes and phenothi-azines are metabolized following a very similar pathway. Compared with the phenothiazines, the thioxanthenes are less likely to form phenolic metabolites.84 Chlorpromazine undergoes extensive first-pass metabolism yielding numerous metabolites. Numerous sites of attack by microsomal CYP450 system (especially CYP2D6) are possible, and most of these reactions happen to various degrees.85,86 Several metabolites have been isolated and characterized. Phase I reactions include oxidative N-demethylation to give primary and secondary amines, aromatic hydroxylation that yields phenols, side chain tertiary amine oxidation that affords Noxide metabolites, S-oxidation to give sulfoxide and sulfones, oxidative deamination that yields side chain carboxylic acids, and N-10 dealkylation to give chlorophenothiazine. Most of these metabolites are subject of further reactions similar to those already mentioned. From the 168 proposed metabolites, only 45 have been isolated, and the 7-hydroxy-chlorpro-mazine metabolite has been evaluated and found to be effective in schizophrenia. More recently, the sulfoxide metabolite was found to have a diminished therapeutic response.87,88 Excretion is primarily via the kidneys with less than 1% of a dose excreted unchanged in the urine and 20% to 70% as conjugated or unconjugated metabolites. Approximately 5% of a dose is excreted in feces via biliary elimination. Some metabolites can still be detected up to 18 months after discontinuation of long-term therapy.
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