The metabolites of chlorpromazine N-oxide in rat bile

Abstract

1. The metabolism of chlorpromazine N-oxide was studied in female rats after a 20 mg/kg single i.p. dose.

2. Metabolites identified in urine and faeces were chlorpromazine, 7-hydroxy-chlorpromazine, chlorpromazine sulphoxide, N-desmethylchlorpromazine and N-desmethylchlorpromazine sulphoxide. As these same five metabolites were previously shown to be present after oral administration this indicates that reduction of chlorpromazine N-oxide occurs not only in the gastrointestinal tract but also at other sites.

3. The metabolism of chlorpromazine N-oxide was studied following its administration by either i.p., i.v. or oral routes to female rats in which the bile duct was cannulated.

4. There were no qualitative differences between the three routes of administration with respect to the metabolites identified. With the exception of the absence of N-desmethylchlorpromazine and N-desmethylchlorpromazine sulphoxide, all metabolites previously identified in urine and faeces were also present in bile.

5. Additionally there were three compounds present in rat bile which were not identified in urine or faeces. These were chlorpromazine N-oxide, chlorpromazine N, S-dioxide and 7-hydroxychlorpromazine O-glucuronide. This is the first unequivocal evidence for the identification of intact 7-hydroxychlorpromazine O-glucuronide in any species.

6. The inability to detect chlorpromazine N-oxide and chlorpromazine N, S-dioxide in the faeces of rats is likely to be due to the reduction of the N-oxide group on the passage of these biliary metabolites down the intestinal tract.