chlorpromazine-n-oxide and opromazine

Antibodies specific to chlorpromazine N-oxide (CPZNO) were produced in rabbits immunized with a hapten-bovine serum albumin conjugate, which was prepared by linking the 7-position of the phenothiazine ring of the metabolite to the protein via a 4-carbon bridge. An extraction radioimmunoassay (RIA) was developed using this antiserum and shown to have adequate sensitivity and specificity for determination of plasma concentrations of CPZNO in the presence of chlorpromazine (CPZ) and its major metabolites. It was used together with the previously developed RIAs for CPZ, chlorpromazine sulfoxide (CPZSO), and 7-hydroxychlorpromazine (7-OHCPZ) to study the pharmacokinetics of CPZ and these metabolites in five healthy volunteers after they received a single 50-mg oral dose of CPZ. It is interesting to note that peak plasma concentrations of CPZNO were considerably higher than CPZ, and the apparent elimination half-lives of this metabolite were shorter than those of CPZ.

Topics: Adult; Chlorpromazine; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Half-Life; Humans; Male; Plasma; Radioimmunoassay; Spectrophotometry, Ultraviolet

A new high-performance liquid chromatographic (HPLC) procedure for the simultaneous determination of chlorpromazine and its six metabolites, namely, 7-hydroxy-chlorpromazine, N-monodesmethyl-chlorpromazine, 7-hydroxy-N-monodesmethyl-chlorpromazine, chlorpromazine-sulfoxide, chlorpromazine N-oxide, and N-monodesmethyl-chlorpromazine-sulfoxide, in plasma was developed and compared with four radioimmunoassay (RIA) procedures that measured separately chlorpromazine, 7-hydroxy-chlorpromazine, chlorpromazine-sulfoxide, and chlorpromazine N-oxide. The results of this study for the determination of plasma levels in four healthy volunteers given a 100-mg single oral dose of chlorpromazine hydrochloride demonstrated that in some cases, strong correlations could be found between the plasma levels determined by the HPLC and RIA procedures, whereas in other cases, there was a lack of strong correlation. The discrepancies observed were not only due to nonspecificity of the immunoassay procedures employed, but also to a lack of rigorous specificity of the HPLC procedure in plasma samples from dosed humans. These findings clearly indicate that even a chemical method of analysis, such as HPLC, has its limitations in its application to multianalyte analysis, as is the case with drugs like chlorpromazine.

Topics: Chlorpromazine; Chromatography, High Pressure Liquid; Male; Monitoring, Physiologic; Radioimmunoassay; Regression Analysis

Chlorpromazine (CPZ), chlorpromazine sulfoxide (CPZSO), and chlorpromazine N-oxide (CPZNO) were each incubated (37 degrees C), for various timed intervals up to 60 min, with pooled human whole blood. Plasma and red blood cells were then separated and analyzed by a high performance liquid chromatographic method that avoids the use of alkaline extraction procedures. It was found that CPZ, CPZSO, and CPZNO were remarkably stable in whole blood under physiological conditions. CPZ was converted into CPZSO to a small extent (1%). Reports of 15-50% conversion of CPZ into CPZSO are largely due to artifacts, which result when red blood cell materials come into contact with alkali. CPZNO was recovered (85%) unchanged from the plasma. A small portion (1%) of the CPZNO was reduced to CPZ in the red blood cells. Thus, on the basis of these in vitro data, blood does not appear to be an important tissue for the metabolism of CPZ, CPZSO, or CPZNO.

Topics: Biotransformation; Chlorpromazine; Chromatography, High Pressure Liquid; Erythrocytes; Humans

Pooled plasma from healthy volunteers was spiked with pure, synthetic chlorpromazine (CPZ), chlorpromazine sulfoxide (CPZSO), or chlorpromazine N-oxide (CPZNO), and then made alkaline with either sodium hydroxide or sodium carbonate. The samples were allowed to stand at room temperature for various timed intervals before extraction with organic solvent. It was found that CPZNO was reduced to CPZ in plasma made alkaline with sodium hydroxide, but not in protein-free buffer solution at high pH nor in plasma made alkaline with sodium carbonate. The reaction appears to take place through reducing equivalents generated by the action of sodium hydroxide on plasma proteins. Thus, apparent concentrations of CPZ in plasma from patients were elevated by as much as 343% when sodium hydroxide was used compared with concentrations in aliquots of the same plasma samples alkalinized with sodium carbonate. The amount of CPZ produced from CPZNO depends on the type of extraction procedure employed as well as on the quantity of sodium hydroxide added to the plasma. By contrast, no interconversion between CPZ and CPZSO or CPZNO and CPZSO was observed in plasma alkalinized and extracted under any of the conditions tested.

Topics: Chlorpromazine; Chromatography, High Pressure Liquid; Humans; Monitoring, Physiologic; Time Factors

Pooled whole blood from healthy volunteers was spiked with pure, synthetic chlorpromazine, chlorpromazine sulfoxide, or chlorpromazine N-oxide and then made alkaline with either sodium hydroxide or sodium carbonate. The addition of alkali causes lysis of red cells, the contents of which spill into the plasma. The lysed samples were allowed to stand at room temperature for various timed intervals before extraction with organic solvents and analysis by high performance liquid chromatography. It was found that a portion (10-14%) of the chlorpromazine spike was oxidised to chlorpromazine sulfoxide, whether the blood was made alkaline with sodium hydroxide or sodium carbonate. Chlorpromazine N-oxide added to whole blood was entirely destroyed in the presence of alkali. The chlorpromazine N-oxide was rapidly reduced to chlorpromazine, a portion of which subsequently underwent oxidation to chlorpromazine sulfoxide. We have found that chlorpromazine N-oxide resides almost entirely in the plasma with only a small portion (less than 4%) distributed into the red cells. Hence, it is essential that red cells and plasma be separated before analysis. Chlorpromazine and chlorpromazine N-oxide can then be extracted from plasma by a method that does not lead to reduction of chlorpromazine N-oxide. Alkaline extraction methods must be avoided in the analysis of chlorpromazine in the red cell fraction.

Topics: Chlorpromazine; Chromatography, High Pressure Liquid; Humans; Time Factors