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  • 1
    Electronic Resource
    Electronic Resource
    Steady-state concentrations of imipramine and its metabolites in relation to the sparteine/debrisoquine polymorphism (1986)
    Springer
    European journal of clinical pharmacology 30 (1986), S. 679-684 
    Details
    ISSN: 1432-1041
    Keywords: imipramine ; sparteine ; desipramine ; drug oxidation ; monogenic polymorphism ; debrisoquine ; therapeutic outcome
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Thirty-five imipramine treated patients were phenotyped with regard to polymorphic drug oxidation using sparteine and/or debrisoquine. During treatment with 100 mg imipramine per day the mean steady-state concentrations and ratios in 28 extensive metabolizers were: imipramine 169 nmol/l; desipramine 212 nmol/l; 2-OH-imipramine/imipramine 0.25; 2-OH-desipramine/desipramine 0.57. The corresponding values in two poor metabolizers were: imipramine 455 and 302 nmol/l; desipramine 1148 and 1721 nmol/l; 2-OH-imipramine/imipramine 0.06 and 0.05; 2-OH-desipramine/desipramine: 0.09 and 0.04 respectively. The metabolic ratios (MR) sparteine/dehydrosparteine and debrisoquine/4-OH-debrisoquine (% of dose in 12-h urine samples) correlated poorly with the imipramine steady-state concentrations during administration of 100 mg per day, but quite well with the desipramine steady-state concentrations. Significant negative correlations were found between sparteine and debrisoquine MR and the 2-OH-imipramine/imipramine and 2-OH-desipramine/desipramine ratios. In most patients the initial dose was changed to obtain concentrations in the therapeutic range, and concentrations for imipramine + desipramine of (mean ± SD) 713±132 nmol/l were achieved in 33 patients. The therapeutic dose was 50 mg per day in one poor metabolizer and ranged from 50–400 mg per day in 32 extensive metabolizers. There was a weak negative correlation between sparteine MR and daily dose. Treatment with imipramine inhibited metabolism of both sparteine and debrisoquine (MR values about doubled), but did not affect the interpatient correlations.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00608215
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  • 2
    Electronic Resource
    Electronic Resource
    Steady-state levels of imipramine and its metabolites: Significance of dose-dependent kinetics (1986)
    Springer
    European journal of clinical pharmacology 30 (1986), S. 43-49 
    Details
    ISSN: 1432-1041
    Keywords: imipramine ; desipramine ; hydroxymetabolites ; plasma concentration monitoring ; dose-dependent kinetics ; drug interaction ; levomeprazine ; perphenazine ; therapeutic response ; sparteine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Seventeen hospitalized patients (age 39–66 years), received a loading dose of 100 mg imipramine HCl and then 50 mg b.i.d. The 12-h plasma concentration at steady-state varied between 40–637 nmol/l for imipramine, 49–1148 nmol/l for desipramine and 89–1603 nmol/l for imipramine + desipramine. Guided by plasma level monitoring, a final therapeutic plasma level between 548–910 nmol/l for imipramine + desipramine was achieved (therapeutic dose range: 50–400 mg/day). Mean time to reach the therapeutic level was 19 days. The mean 2-OH-imipramine/imipramine ratio was 0.24 and mean 2-OH-desipramine/desipramine ratio was 0.56. There was a significant intrapatient correlation between the two ratios, both during 100 mg imipramine/d and at the therapeutic dose level. A low ratio was associated with high imipramine and particularly with a high desipramine level. Well defined steady state levels were established at two different dose levels in 12 patients and at three dose levels in 5 patients. With increasing dose there was a marked and disproportionate rise in the desipramine level and to some extent in the imipramine level. Saturation of imipramine and desipramine hydroxylation appeared to be responsible for the dose-dependent kinetics. Concomitant treatment with levomepromazine and perphenazine in one patient resulted in a significant rise both in imipramine and desipramine concentration, apparently due to inhibition of the hydroxylation. Eleven out of twelve endogenously depressed patients responded completely to treatment, whereas the response was poor in the non-endogenously depressed patients despite optimal drug levels.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00614194
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    Quinidine inhibits the 2-hydroxylation of imipramine and desipramine but not the demethylation of imipramine (1989)
    Springer
    European journal of clinical pharmacology 37 (1989), S. 155-160 
    Details
    ISSN: 1432-1041
    Keywords: imipramine ; desipramine ; quinidine ; sparteine oxidation ; cytochrome P450 isoforms ; genetic polymorphism ; drug interaction ; metabolic clearance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary On separate occasions 6 extensive metabolizers of sparteine took a single oral dose of 100 mg imipramine and desipramine before and during the intake of quinidine sulphate 200 mg/day. During quinidine the total oral clearance of imipramine on average was reduced by 35%, and that of desipramine by 85%. The clearance of imipramine via demethylation was not significantly reduced during quinidine administration, whereas its clearance by other pathways, largely 2-hydroxylation, was reduced by more than 50%. 2-OH-Imipramine and 2-OH-desipramine were detected in plasma before (maximum concentrations 30–100 nmol · l−1) but not during quinidine. It appears that quinidine is a potent inhibitor of the sparteine/debrisoquine oxygenase, P450dbl, which is responsible for the 2-hydroxylation of imipramine and desipramine, but not of the P450 isozyme responsible for the demethylation of imipramine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00558224
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    Paper (German National Licenses)
    Fulltext
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