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  • 1
    Electronic Resource
    Electronic Resource
    Kinetics of oral fluphenazine disposition in humans by GC-MS (1983)
    Springer
    European journal of clinical pharmacology 25 (1983), S. 709-711 
    Details
    ISSN: 1432-1041
    Keywords: fluphenazine ; pharmacokinetics ; plasma concentrations ; intersubject differences
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of fluphenazine was investigated in six healthy volunteers following oral administration (5 mg). Using a sensitive and specific GC-MS procedure plasma fluphenazine concentrations were measured up until 32 h after drug administration. Peak plasma concentrations varied widely (range: 0.26–1.06 ng/ml) and were observed at 2.8±0.5 h following fluphenazine administration. The apparent terminal elimination half-life of fluphenazine was 33.1±8.1 h. The area under the plasma concentration-time curve differed widely between subjects (range: 7.1–28.6 ng/ml h) suggesting large interindividual differences in the extent of fluphenazine presystemic elimination.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542363
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  • 2
    Electronic Resource
    Electronic Resource
    Interconversion between haloperidol and reduced haloperidol in healthy volunteers (1989)
    Springer
    European journal of clinical pharmacology 37 (1989), S. 45-48 
    Details
    ISSN: 1432-1041
    Keywords: haloperidol (HAL) ; reduced haloperidol (RHAL) ; interconversion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The interconversion between haloperidol (HAL) and reduced haloperidol (RHAL) was examined following their separate administration in low (5 mg) single oral doses to 15 young healthy male volunteers in a crossover design. Using an ultrasensitive HPLC method plasma concentrations of HAL and RHAL were monitored over a period of one week following each administration. Except in one case, both the analytes were found in the plasma of all the volunteers following each administration, thereby indicating interconversion of the two compounds. Comparison of the AUC(0-t) ratios of RHAL/HAL and HAL/RHAL following administration of HAL and RHAL, respectively, revealed that the interconversion favours the reduction of HAL to RHAL. The disposition of HAL following administration of RHAL appears to be limited by its rate of formation and the disposition of RHAL following administration of HAL, on the other hand, is much slower than that of the parent compound.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00609423
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  • 3
    Electronic Resource
    Electronic Resource
    Quinidine but not quinine inhibits in man the oxidative metabolic routes of methoxyphenamine which involve debrisoquine 4-hydroxylase (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 471-474 
    Details
    ISSN: 1432-1041
    Keywords: Methoxyphenamine ; Quinidine ; Quinine ; genetic polymorphism ; metabolic inhibition ; drug interaction ; cytochrome P450 isoforms
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Healthy male volunteers (n=13) took a single oral dose of 60.3 mg of methoxyphenamine HCl with and without prior administration of either quinidine (250 mg as bisulphate salt) or its diastereomer quinine (300 mg as sulphate salt). Methoxyphenamine and its N-desmethyl, O-desmethyl and aromatic 5-hydroxy metabolites were quantified in the 0–32 h urine. The oxidative routes of methoxyphenamine metabolism which had been previously shown to involve debrisoquine 4-hydroxylase, namely O-demethylation and 5-hydroxylation were both significantly inhibited by quinidine in the 12 extensive metabolizers. The inhibition was selective in that N-demethylation which does not involve this isozyme was not affected by quinidine. In all but one of these volunteers the methoxyphenamine/O-desmethylmethoxyphenamine ratio changed such that extensive metabolizers could be classified as poor metabolizers due to quinidine pretreatment. No marked change occurred in the renal excretion of methoxyphenamine and its three metabolites either in the extensive metabolizers because of quinine pretreatment or in the poor metabolizer because of treatment with either quinidine or quinine. Thus in the extensive metabolizer phenotype it was demonstrated in one study that enzyme inhibition of quinidine was selective in terms of the metabolic pathways inhibited as well as stereoselective with respect to the inhibitor.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00626372
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  • 4
    Electronic Resource
    Electronic Resource
    Effect of quinidine on the interconversion kinetics between haloperidol and reduced haloperidol in humans: implications for the involvement of cytochrome P450IID6 (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 433-438 
    Details
    ISSN: 1432-1041
    Keywords: Haloperidol ; Cytochrome P450 isozymes ; reduced haloperidol ; interconversion ; quinidine ; drug interaction ; drug metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Haloperidol (HAL) is a potent butyrophenone antipsychotic agent which is reversibly metabolized to reduced haloperidol (RHAL). In order to determine if this reversible metabolic pathway is linked to the debrisoquine 4-hydroxylase isozyme of cytochrome P-450 (P450IID6), HAL (5 mg) or RHAL (5 mg) was orally administered to healthy male volunteers in a randomized crossover design both with and without a prior (1 h) oral dose of quinidine (250 mg bisulfate), a potent inhibitor of this isozyme. Thirteen volunteers, 11 extensive metabolizers, 2 poor metabolizers, completed all four phases of the study. Plasma samples harvested over seven days were analysed for HAL and RHAL. An expression for the apparent fractional availability of metabolite from the parent compound given (Fapp infm supp ) was derived and was used to determine whether HAL or RHAL is the preferred metabolite, and whether quinidine co-administration alters Fapp for either compound. The AUC (0-t) for both HAL and RHAL were significantly greater following the administration of either compound with quinidine compared with AUC (0-t) values obtained in the absence of quinidine. The maximum plasma concentration (Cmax) of the administered compound was also greater following the administration of quinidine. Quinidine had no effect on the half-lives of the administered compounds. The Fapp for HAL and RHAL were not significantly affected by the administration of quinidine, indicating that the interconversion of HAL and RHAL is not linked to P450IID6. The Fapp of RHAL after administration of HAL was significantly greater than the Fapp of HAL after RHAL administration, indicating that RHAL is the preferred metabolic form. This difference was not affected by quinidine. It is concluded that: 1) RHAL is the preferred form after administration of either compound and is not affected by quinidine, 2) the interconversion of HAL and RHAL is not affected by quinidine, indicating that this reversible metabolic process is not linked to P450IID6 and 3) there is a significant increase in the AUC (0-t) and Cmax values following quinidine co-administration with either HAL or RHAL. The precise mechanism of this interaction can not be established from this study, however, the observed increases in AUC (0-t) and Cmax may be explained with a simple tissue blinding displacement mechanism.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315539
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  • 5
    Electronic Resource
    Electronic Resource
    Quinidine inhibits the 7-hydroxylation of chlorpromazine in extensive metabolisers of debrisoquine (1996)
    Springer
    European journal of clinical pharmacology 50 (1996), S. 121-128 
    Details
    ISSN: 1432-1041
    Keywords: Key words Chlorpromazine ; CYP2D6; 7-hydroxychlorpromazine ; quinidine ; polymorphic metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Quinidine 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-desmethylmethoxyphenamine metabolic ratio. Quinidine significantly decreased the urinary excretion of 7-hydroxylchlorpromazine 2.2-fold. Moreover the urinary excretion of this metabolite correlated inversely (r s = −0.80) with the metabolic ratio. The urinary recoveries of chlorpromazine, chlorpromazine N-oxide, 7-hydroxy-N-desmethylchlorpromazine, N-desmethylchlorpromazine 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 (α = 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050079
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  • 6
    Electronic Resource
    Electronic Resource
    Stereoselective pharmacokinetics of doxepin isomers (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 539-544 
    Details
    ISSN: 1432-1041
    Keywords: Doxepin ; N-desmethyldoxepin ; stereoselective pharmacokinetics ; stereoselective metabolism ; Cis isomer ; trans isomer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Commercial preparations of the tricyclic antidepressant doxepin contain 15% of the more active cisdoxepin and 85% of the trans-isomer. The single dose pharmacokinetics of doxepin and its major metabolite N-desmethyldoxepin were examined in 30 healthy young men. Results for total doxepin showed wide intersubject variation in all pharmacokinetic parameters except tmax and Cmax. Plasma levels of cis-doxepin were extremely low and it was only possible to estimate the stereoselective pharmacokinetics of the parent drug in 3 subjects. The data from those particular subjects resulted in an average ratio of cis- to trans-doxepin isomers in plasma of 15:85. In contrast, the mean plasma levels of cis-N-desmethyldoxepin in 28 subjects exceeded those of the trans-isomer at every time point after 10 h, such that the areas under the plasma concentration versus time curves (AUC) of cis-N-desmethyldoxepin were significantly higher than those of the corresponding trans-isomer. This phenomenon may play an important role in the therapeutic action of doxepin since it has been suggested that cis-N-desmethyldoxepin is pharmacologically active. In 2 subjects, however, the AUC 0-inf of trans-N-desmethyldoxepin were respectively 4 and 8 fold higher than those of the cis-isomer.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00314865
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  • 7
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of chlorpromazine and key metabolites (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 563-569 
    Details
    ISSN: 1432-1041
    Keywords: Chlorpromazine ; metabolites ; N-oxide ; sulfoxide ; 7-hydroxy ; conjugates ; pharmacokinetics ; first pass metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A study was carried out in 11 healthy young men to investigate the pharmacokinetics of chlorpromazine (CPZ) after a bolus intravenous (IV) dose (10 mg) and three single oral doses (25, 50 and 100 mg), with a washout period of two weeks between doses. Plasma levels of CPZ, CPZ N-oxide (CPZNO), CPZ sulfoxide (CPZSO) and both free and conjugated 7-hydroxy-CPZ (7-HOCPZ) were measured by extraction radioimmunoassays. CPZ exhibited multicompartmental pharmacokinetics in most subjects. There was wide between-subject variability in half life (11.05 h), volume of distribution (1215 l), volume of distribution at steady state (642 l) and mean residence time (8.88 h), whereas systemic clearance was somewhat less variable (76.6 l·h−1). All metabolites were present in measurable concentrations in the plasma of 9 of 11 subjects after IV CPZ, whereas free 7-HOCPZ was not detected in the other 2 individuals. With the exception of CPZNO, the biological half lives of the primary metabolites were longer than the half life of CPZ. After oral administration, the percentage of CPZ reaching the systemic circulation intact (F%) was very low (4–38%) and dose dependant. Moreover, both within-subject and between-subject variances were very high. The maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve extrapolated to infinite time (AUC) showed evidence of nonlinearity, whereas half life did not appear to be dose dependant. These data suggest that the high degree of variability in the pharmacokinetics of CPZ is a result of extensive first pass metabolism rather than variation in half life. The mean AUC for the total conjugates of 7-HOCPZ was about two fold higher than that of the parent drug or any other metabolite. This shows that phase II metabolism plays a very significant role in the disposition of CPZ. As a result, the role of CYP2D6 in the 7-hydroxylation of CPZ cannot be fully assessed without taking phase II metabolism into account.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315316
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  • 8
    Electronic Resource
    Electronic Resource
    An Approach for Widening the Bioequivalence Acceptance Limits in the Case of Highly Variable Drugs (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1865-1868 
    Details
    ISSN: 1573-904X
    Keywords: bioequivalence ; highly variable drug ; intrasubject variability ; acceptance limits
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Highly variable drugs pose a problem in bioequivalence assessment because they often fail to meet current regulatory acceptance criteria for average bioequivalence (80–125%). This paper examines alternative approaches to establishing bioequivalence. Methods. Suggested solutions have included alternate study designs, e.g., replicate and multiple dose studies, reducing the level of the confidence interval, and widening the acceptance limits. We focus on the latter approach. Results. A rationale is presented for defining wider acceptance limits for highly variable drugs. Two previously described methods are evaluated, and a new method having more desirable properties is proposed. Conclusions. We challenge the “one size fits all” current definition of bioequivalence acceptance limits for highly variable drugs, proposing alternative limits or “goal posts” which vary in accordance with the intrasubject variability of the reference product.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016219317744
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  • 9
    Electronic Resource
    Electronic Resource
    A placebo-controlled trial of fluoxetine added to neuroleptic in patients with schizophrenia (1995)
    Springer
    Psychopharmacology 117 (1995), S. 417-423 
    Details
    ISSN: 1432-2072
    Keywords: Fluoxetine ; Schizophrenia ; Neuroleptics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Following a 2-week placebo lead-in, schizophrenic patients were randomly assigned to fluoxetine 20 mg/day or placebo added to depot neuroleptic for a 6-week, double blind trial. All patients had received a stable dose of depot neuroleptic for at least 6 months and did not meet criteria for depression. Serum samples were obtained at baseline and at weeks 4 and 6. Scores on the negative symptom subscale of the Brief Psychiatric Rating Scale (BPRS) were significantly lower at week 6, controlling for baseline scores, in patients receiving fluoxetine (n=20) compared to patients receiving placebo (n=21). Measures of psychosis, depression, global functioning and extrapyramidal symptoms (EPS) did not differ between groups at week 6. Fluoxetine administration was associated with a mean 65% increase in serum fluphenazine concentrations in 15 patients and a mean 20% increase in serum haloperidol concentrations in three patients. The change in negative symptoms at week 6 did not correlate with serum concentrations of fluoxetine or norfluoxetine, but did inversely correlate withS-norfluoxetine, an active stereoisomer of fluoxetine. For these chronically ill patients, fluoxetine significantly improved negative symptoms and did not worsen EPS, despite causing substantial elevation in serum concentrations of neuroleptics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02246213
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  • 10
    Electronic Resource
    Electronic Resource
    The elucidation of the mass spectral fragmentation pathway of α-methyldopamine derivatives by chlorine labelingTFA = trifluoroacetyl; TFAA = trifluoroacetic anhydride; CFAA = monochlorodifluoroacetic anhydride. (1979)
    Chichester : Wiley-Blackwell
    Biological Mass Spectrometry 6 (1979), S. 554-558 
    Details
    ISSN: 0306-042X
    Keywords: Chemistry ; Analytical Chemistry and Spectroscopy
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The mass spectra of the tristrifluoroacetyl derivative of α-methyldopamine and the bistrifluoroacetyl derivative of 3-O-methyl-α-methyldopamine contain important ions which can be rationalized by two alternative fragmentation pathways. These ambiguities were resolved by means of a simple chemical derivatization technique. The labile phenolic ester groups were hydrolyzed and subsequently re-esterified by reaction with chlorodifluoroacetic anhydride in the presence of ethyl acetate thereby labeling ions containing ester group(s) in the mass spectra with the diagnostic chlorine isotope ratio. This resulted in the addition of 16/18 mass units to the weights of the ions for each fluorine atom replaced by chlorine. Since it was easy to distinguish loss of the mass of a neutral molecule of trifluoroacetamide (113 mass units) from the ions of a chlorodifluoroacetoxy radical (129 mass units), the elimination of trifluoroacetamide was distinguished from that of trifluoroacetoxy radical. Derivatives were also prepared in which the chlorine label was located on the N-acyl function. The mass spectra of the chlorine labeled compounds showed that the major fragmentation pathway of tristrihaloacetyl-α-methyldopamine and bistrihaloacyl-3-O-methyl-α-methyldopamine is by loss of a neutral molecule of trihaloacetamide.
    Additional Material: 2 Tab.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/bms.1200061204
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