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Quindine is a potent inhibitor of CYP2D6 (debrisoquine 4-hydroxylase). Its effect on the disposition of chlorpromazine was investigated in ten healthy volunteers using a randomised crossover design with two phases. A single oral dose of chlorpromazine hydrochloride (100 mg) was given with and without prior administration of quinidine bisulphate (250 mg). Chlorpromazine and seven of its metabolites were quantified in the 0- to 12-h urine while plasma concentrations of chlorpromazine and 7-hydroxychlorpromazine were measured over 48 h. All volunteers were phenotyped as extensive metabolisers with respect to CYP2D6 using the methoxyphenamine/O-desmethyl-methoxyphenamine metabolic ratio. Quinidine significantly decreased the urinary excretion of 7-hydroxylchlorpromazine 2.2-fold. Moreover the urinary excretion of this metabolite correlated inversely (rs = -0.80) with the metabolic ratio. The urinary recoveries of chlorpromazine, chlorpromazine N-oxide, 7-hydroxy-N-desmethylchlorpromazine, N-desmethyl-chlorpromazine sulphoxide and the total of all eight analytes were unaltered by quinidine. However, quinidine administration caused significant increases in the urinary excretions of chlorpromazine sulphoxide, N-desmethylchlorpromazine and N, N-didesmethylchlorpromazine sulphoxide, which indicated that compensatory increase in these metabolic routes of chlorpromazine might have been responsible for the lack of change observed in the urinary recovery of the parent drug. Quinidine administration produced modest decreases (1.2- to 1.3-fold) in the mean peak plasma concentrations and mean areas under the plasma concentration-time curves of 7-hydroxychlorpromazine and increases (1.3- to 1.4-fold) in these parameters for the parent drug chlorpromazine, but none of these changes reached statistical significance. Based on ANOVA the sample sizes required to detect these differences as significant (alpha = 0.5) with a probability of 0.8 were determined to vary between 15 and 42. These data suggest that CYP2D6 is involved in the metabolism of chlorpromazine to 7-hydroxychlorpromazine. However, genetic polymorphism in this metabolic process did not play a dominant role in accounting for the extremely large interindividual variations in plasma concentrations encountered with this drug.

1. Metabolic N(+)-glucuronidation of aliphatic tertiary amine antidepressant or antipsychotic drugs was investigated in man. In each case, urine was collected either from patients and/or from healthy volunteers who were administered the drug orally. 2. Metabolites were separated by hplc and individually collected prior to mass spectrometric analysis in the fast atom bombardment mode. The structure of each metabolite identified as a quaternary ammonium-linked glucuronide metabolite was confirmed by direct comparison of its mass spectrum and chromatographic behaviour with that of an authentic standard synthesized in these laboratories. 3. Of the 10 antipsychotic drugs examined clozapine and loxapine were the only two for which the N(+)-glucuronidation pathway was observed, whereas all four antidepressants gave the respective N(+)-glucuronide metabolite. 4. The N(+)-glucuronide metabolites in 24 h urine samples were quantified by hplc. The mean (n = 3) percentage of the dose excreted as the metabolite was found to be 1.6 and 3.1% in the cases of the antipsychotic agents loxapine and clozapine respectively, whereas for the antidepressants clomipramine, imipramine, trazodone and trimipramine these means varied between 0.1 and 0.8%.

Whereas some metabolites of antipsychotic drugs are psychoactive and contribute to clinical improvement, recent studies have provided evidence that certain metabolites contribute to side-effects which can be disabling enough to negate clinical improvement as regards the psychosis. The route of administration of the drug can determine the amount of metabolite produced in the body and affect how the patient feels in response to the treatment.

1. The metabolism of sulforidazine was studied in female dogs and adult male humans after oral administration of 37.5 mg and 25.0 mg, respectively. 2. Metabolites in organic extracts of dog urine were separated by h.p.l.c. and individually collected prior to mass spectrometric analysis, while organic extracts of human urine were directly subjected to plasmaspray h.p.l.c.-mass spectrometric determination. In the case of phenolic metabolites, the urinary extracts from both species were derivatized with a silylating reagent (with or without prior enzymic hydrolysis) and subsequently analysed by h.p.l.c.-mass spectrometry. The structures of metabolites with the exception of phenols were confirmed by comparison of their mass spectra and chromatographic behaviours with those of authentic standards. 3. The compounds identified in urine of both species were sulforidazine, two diastereomers of sulforidazine ring sulphoxide, the lactam of sulforidazine ring sulphoxide and a phenolic derivative of sulforidazine, whereas sulforidazine N-oxide and the lactam of sulforidazine were identified only in human urine. Moreover the phenolic metabolite was present in human urine in both unconjugated and conjugated forms, whereas dog urine had only the conjugated form. 4. Sulforidazine and some of its major metabolites were quantified by an h.p.l.c. method. The mean urinary excretions (0-48 h) of sulforidazine were similar in human (n = 3) and dog (n = 3) (5.9 +/- 0.7% and 7.2 +/- 1.9%), as were the excretions of sulforidazine ring sulphoxide (13.2 +/- 4.6% and 13.3 +/- 4.4%), while the lactam of sulforidazine ring sulphoxide was a major metabolite only in human (7.5 +/- 2.8% and < 0.1%). The lactam of sulforidazine was a minor metabolite in human. 5. The metabolites observed in human urine were similar to those previously reported in rat, except that sulforidazine N-oxide was found only in human, whereas the two diastereomers of N-desmethylsulforidazine ring sulphoxide were observed only in rat. These data suggest that rat may be a more suitable animal than dog for further study of the metabolism of the piperidine ring of sulforidazine.

1. The metabolism of mesoridazine was studied in female rats (20 mg/kg, oral), female dogs (50 mg over 30 h, oral) and adult male volunteers (25 mg, oral). 2. Solvent extracts of urines from each species were directly analysed by h.p.l.c.-mass spectrometry with a plasmaspray interface. In the case of phenolic metabolites the urinary extracts were derivatized with a silylating reagent (with and without prior enzymic hydrolysis) prior to analysis. The structures of metabolites, with the exceptions of mesoridazine N-oxide and phenols, were confirmed by comparison of their chromatographic behaviours and mass spectra with those of authentic standards. 3. Compounds identified in the urine of all three species were mesoridazine, sulforidazine, mesoridazine ring sulphoxide, sulforidazine ring sulphoxide, N-desmethylmesoridazine ring sulphoxide, the lactam of sulforidazine ring sulphoxide and phenolic derivatives of mesoridazine and sulforidazine. Whereas the unconjugated phenolic metabolite of sulforidazine was present in urine of all three species, the conjugated form was identified only in dog and rat urines. Also, the unconjugated phenolic metabolite of mesoridazine was identified only in the urine of dog and human, but rat urine contained only the conjugated form. 4. Other metabolites found were: the lactam of mesoridazine (rat), the lactam of mesoridazine ring sulphoxide (rat and human), mesoridazine N-oxide (human) and sulforidazine N-oxide (dog and human). 5. Mesoridazine and six of its metabolites present in urines of human, rat and dog were quantified by a h.p.l.c.-u.v. method. The mean total excretion of measured analytes in human, rat and dog were 6.3, 2.6 and 29.1%, respectively. The excretion of the lactam of sulforidazine ring sulphoxide was greater in human (0.4%) and rat (0.2%) than dog (0.02%). Moreover, the urinary excretion of the lactam of mesoridazine ring sulphoxide in human and rat constituted 0.4% and 0.2%, respectively. Of the three lactams found in rat the lactam of mesoridazine was present in the least amount (0.05%). 6. Interspecies comparison of the lactam metabolites indicated that both qualitatively and quantitatively human more closely resembled rat than dog. On the other hand, N-oxide metabolites were detected in human and dog but not in rat.