QUANTIFICATION AND PROBABLE STRUCTURE, IN HUMAN URINE, OF THE NONPHENOLIC AND PHENOLIC METABOLITES OF CHLORPROMAZINE

¹ Clinical Neuropharmacology Research Center, National Institute of Mental Health, St. Elizabeths Hospital, Washington, D. C.

Methods have been described for the estimation of individual and grouped metabolites of chlorpromazine in human urine using the techniques of quantitative paper chromatography and the reaction with methyl orange, respectively. Eight 24-hour urines and an additional incomplete 24-hour specimen, all from patients receiving chlorpromazine chronically, were analyzed. Comparison was made with that of urine obtained from two individuals receiving a single dose of chlorpromazine, and six control individuals not receiving chlorpromazine.

The nonphenolic metabolites included unchanged chlorpromazine, chlorpromazine-N-oxide, chlorpromazine sulfoxide, and the mono- and di-N-demethylated sulfoxides. The first three were minor and the latter predominant.

The monophenolic metabolites included a chlorpromazine monophenol, its mono- and di-N-demethylated derivatives and a compound which appeared to be neutral. The mono-N-demethylated compound may have predominated in the series of the amines. Glucuronide conjugates of these compounds predominated over the nonconjugated forms. No evidence was obtained for the presence of phenol sulfates or for methylated phenols. Phenolic metabolites predominated over the nonphenolic metabolites by a ratio of about 2-3 to 1.

Based on both this work and the work of Fishman and Goldenberg (1963), the most probable ring structures of the monophenols are the 2-chloro-7- or 2-chloro-8-hydroxy ring structures.

A di-oxygenated metabolite is present which was extractable primarily into butanol after hydrolysis with -glucuronidase. Only a crude approximation to its structure could be suggested.

Deviation from the general quantitative pattern was seen in two cases at the higher doses: a reduced ratio of demethylated to nondemethylated metabolites in one patint and a reduced ratio of phenolic to nonphenolic metabolites in the other.

Urine of two individuals receiving a single dose of chlorpromazine contained predominantly the nonphenolic metabolites.

A significant trend toward decreased percent recovery of metabolites in the urine with increasing dose of drug was noted. There was no correlation, under the conditions of chronic drug administration, between the ratio of phenolic to nonphenolic metabolites and drug dose.

3-Hydroxypromazine was shown to be a metabolite of promazine. Qualitatively, at least, the metabolism of promazine was similar to that of chlorpromazine.

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