THE METABOLISM OF CHLORPROMAZINE N-OXIDE IN MAN AND OTHER SPECIES
Date
1989
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
Type
Degree Level
Doctoral
Abstract
It has been well established that N-oxidation is one of the major routes of metabolism for the tertiary amine functional group. However, the contribution of N-oxidation to the elimination of these compounds is difficult to assess due to the simultaneous occurrence of metabolic reduction in vivo. The existence of reactions that regene-rate the parent drug from a metabolite are generally recognized but this aspect of drug metabolism has received relatively little attention under in vivo conditions. Upon administration of a phenothiazine antipsychotic agent such as chlorpromazine in both single doses and multiple doses, high blood levels of the N-oxide metabolite result. The metabolic conversion of chlorpromazine N-oxide back to the parent drug has been established, but metabolic studies of chlorpromazine N-oxide itself are lacking. Therefore, studies were conducted to identify the metabolites in urine and feces after oral administration of chlorpromazine N-oxide to rat, dog and man. In addition, subsequent studies were carried out in the rat to answer some of the questions generated as a result of the experiment involving oral administration of chlorpromazine N-oxide to this species.
The N-oxide compounds were synthesised and an extraction procedure developed which took into considera-tion the labile and polar nature of the kt-oxide group. In most cases metabolites were separated and identified by HPLC, MS or HPLC - MS techniques and compared to authentic reference standards. The results of the oral administration experiments in rat, dog and man indicated that all three species extensively metabolized chlorpromazine N-oxide with at least five metabolites being identified in both urine and feces of each species. The metabolic pattern of dog and man were more closely related than those of rat and man. For example, in dog and man compounds which retained the N-oxide group (chlorpromazine N-oxide and chlorpromazine N,S-dioxide) were identified in the excreta (especially urine), no such compounds could be detected in the urine or feces of the rat. Upon administration of 3H-chlorpromazine N-oxide orally to rats (n = 5), it was discovered that much of the radioactivity was eliminated through urine (26.9 + 7.2%) and feces (52.1 + 9.7%) after three and four days, respectively. Thus both these routes of elimination are important in the excretion of the administered compound and about twice the amount of drug related material was excreted in the feces as compared to the urine. Upon intraperitoneal administration of chlorpromazine N-oxide, there was no difference as to the metabolites excreted in urine or feces as compared to the results from oral administration. Thus it is likely that reduction of chlorpromazine N-oxide is not limited to the gastroin-testinal tract. Investigation with the aid of biliary cannulation discovered that irrespective of the route of administration (intravenous, intramuscular or oral), the rat eliminated, among other compounds, 7-hydroxychlorproma-zine glucuronide, chlorpromazine N-oxide and chlorpromazine N,S-dioxide; all of which were not identified in the urine nor the feces of the rat. Thus it is likely that neither of the N-oxide containing compounds are detected in feces since subsequent to their excretion in bile they undergo reduction on their transit down the intestinal tract to the colon.
Description
Keywords
CHLORPROMAZINE N-OXIDE
Citation
Degree
Doctor of Philosophy (Ph.D.)
Department
Pharmacy