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1. Commercial doxepin contains geometric isomers in the proportions Z:E = 15:85. Z-doxepin and its metabolite Z-N-desmethyldoxepin are both active antidepressants, whereas the corresponding E-isomers are less active therapeutically. 2. The present pharmacokinetic study was a balanced, randomized, two-treatment, two-period, two-sequence crossover design in which 12 healthy male volunteers were given single doses of commercial doxepin intravenously and orally on two occasions separated by a washout period. 3. A two-compartment model with no lag time and first-order elimination fitted the plasma concentration-time curves after intravenous dosing. Pharmacokinetic parameters estimated from the model were comparable with those estimated by non-compartmental methods. 4. All pharmacokinetic parameters displayed a wide between-subject variability. Both isomers of doxepin showed large volumes of distribution and relatively short half-lives in plasma, suggestive of extensive distribution and/or tissue binding. The mean fraction absorbed after oral administration was 0.29 for each isomer. Renal clearances of each isomer were very low after either oral or intravenous dosing, although all four analytes were quantifiable in the urine for prolonged periods. 5. After oral dosing, plasma concentrations of the doxepin isomers remained roughly in the ratio Z:E = 15:85, whereas those of N-desmethyldoxepin were closer to 1:1 in all but two outliers, who had high levels E-N-desmethyldoxepin.

1. Doxepin is marketed as an irrational mixture of geometric isomers such that the more active Z-isomer comprises only 15% of the total doxepin whereas the less active E-isomer makes up the remaining 85%. 2. The ratio of isomers of the doxepin remains approximately Z:E = 15:85 in the plasma of depressed patients whereas plasma levels of the active Z-N-desmethyl metabolite are similar to those of E-N-desmethyldoxepin. 3. After examination of four animal species (dog, rabbit, guinea pig, rat), rat was closest to human in terms of the Z:E ratio of the geometric isomers of N-desmethyldoxepin excreted in the 0-24-h urine. 4. Changes in the urinary Z:E ratio of the metabolite were observed after oral but not after intravenous or intraperitoneal administration of commercial doxepin to rat. 5. There was no evidence of Z/E interconversion after administration of the pure isomers to rat in vivo, or after incubation of rat or human liver homogenates with pure isomers. 6. In vitro data suggested that the distortion of the Z:E ratio of N-desmethyldoxepin was a consequence of faster metabolism of the E-isomer in comparison with Z-N-desmethyldoxepin rather than 'enrichment' of the Z-isomer at the expense of the E-isomer.

1. The phase II metabolites in the bile, urine and faeces of rat dosed with clozapine were investigated by means of electrospray mass spectrometry (ESMS) in both positive and negative ion modes. 2. When operated at a cone voltage of 45 V, this soft ionization technique permitted the detection of quasi molecular ions of both sulphate and glucuronide conjugates of hydroxylated phase I metabolites of clozapine. With the cone voltage set at 90 V, however, the ESMS also contained highly diagnostic ions resulting from the loss of 80 Daltons (sulphur trioxide) or 176 Daltons (the glucuronide moiety) from sulphates and O-glucuronides respectively. 3. A sufficient quantity of one metabolite was isolated from rat bile to permit further analysis by 1H-nmr. This metabolite, which was also found in rat urine, was proved to be 7-O-glucuronyl-7-hydroxyclozapine. The analogous sulphate metabolite was also identified in bile by ESMS. 4. Correspondingly glucuronide and sulphate conjugates of a hydroxylated N-desmethyl clozapine were similarly detected in rat bile. There was insufficient material to permit analysis by 1H-NMR, but it appears likely that conjugation was also at the 7-position of N-desmethylclozapine. 5. Finally, the sulphate conjugate of a hydroxy dechlorinated derivative of clozapine was identified by ESMS in both urine and bile. By analogy with a previous report of a similar metabolite in man, the metabolite was tentatively identified as 8-hydroxy-8-deschloroclozapine.

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-hydroxychlorpromazine, 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.

1. To expedite direct studies on phase II metabolites of fluphenazine, pure fluphenazine or 7-hydroxyfluphenazine were incubated with a rabbit hepatic microsomal immobilized enzyme system. After purification and recrystallization a high yield (60%) of 7-hydroxy-beta-D-O-glucuronyl-fluphenazine was obtained. 2. The structure of this glucuronide was proven unambiguously by mass spectrometry (fast atom bombardment, daughter ion analysis, electron impact, chemical ionization) and 1H-n.m.r. and 13C-n.m.r. spectroscopy. The phenolic ether glucuronide was the sole product of the reaction. 3. There was no evidence of conjugation at the primary alcohol group of the side-chain of fluphenazine, or of the formation of quaternary ammonium-linked glucuronides with either of tertiary aliphatic nitrogen atoms of the side-chain. 4. Incubation of fluphenazine with the immobilized enzyme system gave a poor yield (less than 1%) of the aliphatic ether glucuronide as reaction product, consistent with a low susceptibility of the side-chain primary alcohol function of fluphenazine to glucuronidation.

1. Two-different double derivatization techniques and two different g.l.c. systems were used to separate isomeric phenolic carboxylic acids in normal human urine. 2. Carboxylic acids were converted into n-butyl esters and phenolic functions into trifluoroacetic acid esters. 3. n-Butyl trifluoroacetoxybenzoates were separated by g.l.c. and detected by mass spectrometric single-ion monitoring. 4. Trifluoroacetates were hydrolysed under mild conditions, and liberated phenolic groups were subjected to flash methylation. 5. n-Butyl methoxybenzoates were separated by g.l.c. and detected by flame ionization. 6. All derivatives were identified by comparison of retention times and mass spectra with those of authentic reference standards. 7. The urine of a normal vegetarian volunteer was examined. 8. The presence of meta- and para-hydroxybenzoic acids, vanillic acid and isovanillic acid was confirmed by unambiguous techniques.

1. The disposition of the hallucinogen 3,4-dimethoxyamphetamine in vivo was examined in dogs and monkeys. 2. O-Demethylation is important since 3-O-methyl-alpha-methyldopamine (3-methoxy-alpha-methyltyramine) was found in the urine of both species, and traces of alpha-methyldopamine were found in the urine of dogs. 3. Also found in the urine of dogs were 1-(3,4-dihydroxyphenyl)propan-2-one and 3,4-dihydroxybenzoic acid, which are side-chain modified metabolites of alpha-methyldopamine. 4. 1-(3-Methoxy-4-hydroxyphenyl)propan-2-one, a side-chain modified metabolite of 3-O-methyl-alpha-methyldopamine, was present in the urine of both dogs and monkeys. 5. The 3-O-demethylated isomers 4-O-methyldopamine and 1-(3-hydroxy-4-methoxyphenyl)propan-2-one were not detected.

1. The metabolism of 3-methoxyamphetamine in vivo was examined in dog, monkey and man. 2. The metabolites identified in all three species were 3-O-methyl-alpha-methyldopamine, 1-(3-methoxy-4-hydroxyphenyl)propan-2-ol, 3-hydroxyamphetamine, 1-(3-hydroxyphenyl)propan-2-one, 1-(3-hydroxyphenyl)propan-2-ol, 1-(3-methoxyphenyl)propan-2-ol and 1-(3-methoxyphenyl)propane-1,2-diol. 3. 1-Hydroxyl-1(3-hydroxyphenyl)propan-2-one was tentatively identified in the urine of all three species. 4. 4-O-Methyl-alpha-methyldopamine was also found in the urine of dog and monkey but not in human urine.