Drugs online research references
Biochem Pharmacol. 1985 Jul 15;34(14):2501-5.
Inhibition of desmethylimipramine 2-hydroxylation by drugs in human liver microsomes.
von Bahr C, Spina E, Birgersson C, Ericsson O, Goransson M, Henthorn T, Sjoqvist F.
The 2-hydroxylation of desmethylimipramine (DMI) correlates strongly with the 4-hydroxylation of debrisoquine (D) both in human volunteers and in vitro comparing human liver microsomes from different individuals. D competitively inhibits the 2-hydroxylation of DMI in vitro suggesting that DMI is hydroxylated by the 'debrisoquine hydroxylase' which is under monogenic control in man. We have characterized the effect of drugs on the hydroxylation of DMI in human liver microsomes by measuring the formation of 2-OH-DMI with HPLC using fluorescence detection. Amitriptyline, nortriptyline and metoprolol inhibited the hydroxylation of DMI competitively indicating interaction with the catalytical site for DMI 2-hydroxylation. Antipyrine and amylobarbitone at concentrations similar to their Km-values for metabolism did not inhibit DMI-hydroxylation. Thus, for these compounds there was a good correspondence between the drugs' capacity to inhibit DMI 2-hydroxylation competitively in vitro and their apparent metabolism by the 'debrisoquine hydroxylase' in vivo in man. Thioridazine, chlorpromazine, quinidine and quinine also inhibited DMI-hydroxylation competitively. Thioridazine was an unusually potent inhibitor (apparent inhibition constant Ki = 0.75 microM). Quinidine was also an unusually potent inhibitor (Ki = 0.27 microM) and much more efficient than its isomer quinine (Ki = 12 microM). Theophylline could inhibit DMI hydroxylation but with atypical kinetics. We suggest that this simple DMI in vitro test as well as earlier described inhibition tests with debrisoquine, sparteine and bufuralol can be used to screen if drugs interact with the 'debrisoquine hydroxylase' in human liver.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=4015690&dopt=Abstract
Clin Pharmacol Ther. 1984 Sep;36(3):343-9.
The nonlinear kinetics of desipramine and 2-hydroxydesipramine in plasma.
Cooke RG, Warsh JJ, Stancer HC, Reed KL, Persad E.
Plasma levels of desipramine (DMI) and the unconjugated form of its principal metabolite 2-hydroxydesipramine (OH-D) were measured under steady-state conditions in nine depressed inpatients during treatment with 75 mg DMI every 12 hr and after at least 1 wk of an increased dose of DMI (after steady state). When DMI dosage was raised after an initial steady state had been reached, the rise in plasma DMI level was proportionately greater than the increase in dosage, suggesting saturation of DMI elimination pathways. Levels of OH-D rose in proportion to dose, suggesting saturation of DMI elimination by 2-hydroxylation could not explain DMI plasma level changes. In contrast, there were no dose-dependent effects on the disposition of amitriptyline or its metabolite nortriptyline in subjects receiving the same amitriptyline dose.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6467794&dopt=Abstract
Pharmacology. 1981;23(2):57-63.
Tricyclic antidepressant determination in human plasma by gas-liquid chromatography using nitrogen-phosphorous detection: application to single-dose pharmacokinetic studies.
Abernethy DR, Greenblatt DJ, Shader RI.
A method with adequate sensitivity (to 0.50-0.75 mg/ml) for single-dose pharmacokinetic studies which utilizes gas-liquid chromatography with nitrogen-phosphorous detection for tricyclic antidepressants (imipramine, desipramine, amitriptyline, nortriptyline, and doxepin) is described. A basic (pH 13) extraction with acid back-wash and subsequent basic reextraction is used for plasma sample preparation. Standard curves, using clomipramine as the internal standard, are linear for concentrations from 1 to 200 ng/ml for all tricyclic antidepressants. Applicability of the method is demonstrated by a pharmacokinetic study in a normal volunteer who received 12.5 mg imipramine hydrochloride i.v.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7312937&dopt=Abstract
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