Clinical pharmacokinetics of imipramine and desipramine in alcoholics and normal volunteers

Department of Psychiatry, Tufts--New England Medical Center, Boston, MA.
Clinical Pharmacology &#38 Therapeutics (Impact Factor: 7.39). 06/1988; 43(5):509-18. DOI: 10.1038/clpt.1988.66
Source: PubMed

ABSTRACT Recently detoxified men with alcohol dependence (n = 15) and healthy volunteers (n = 14) were administered oral and intravenous imipramine and desipramine. Alcoholics had significantly greater total body clearance of imipramine (0.93 vs. 0.48 L/hr/kg; P less than 0.05) and desipramine (1.00 vs. 0.62 L/hr/kg; P less than 0.05) than did control subjects. Intrinsic clearance of unbound imipramine was greater in the alcoholic group (19.80 vs. 6.56 L/hr/kg; P less than 0.05), as was the intrinsic clearance of unbound desipramine (14.52 vs. 9.05 L/hr/kg; P less than 0.05). The mean elimination half-life for imipramine was significantly decreased in alcoholics (8.7 vs. 19.9 hours after intravenous infusion and 10.9 vs. 19.6 hours after oral administration; P less than 0.05). The mean elimination half-life for desipramine was decreased in alcoholics after intravenous infusion (16.5 vs. 22.4 hours; P less than 0.05). Unbound fractions of drug in plasma were decreased in the alcoholic group for both imipramine and desipramine after both routes of administration. alpha 1-Acid glycoprotein levels were elevated in the alcoholic group whereas total protein and albumin levels did not differ between groups. These findings suggest that recently detoxified alcoholics may require higher doses of imipramine than do nonalcoholic subjects. Desipramine clearance was affected to a lesser degree than imipramine, suggesting that from a pharmacokinetic standpoint it may be the preferred drug for the treatment of alcoholics with depression. Periodic monitoring of plasma levels may be required for recently abstinent alcoholics treated with antidepressants.

1 Bookmark
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Metabotropic glutamate 5 (mGlu5) receptors are functionally connected with NMDA receptors. The antidepressant activity of the NMDA receptor antagonist ketamine in both preclinical and clinical studies, along with the antidepressant-like activities of negative allosteric modulators (NAMs) of mGlu5, led us to investigate if prolonged administration of various antidepressant drugs or the mGlu5 NAM, MTEP, causes changes in mGlu5 receptor availability or protein expression or in expression of Homer proteins in the rat brain. Our results clearly show that prolonged treatment with antidepressants with various mechanisms of action (such as escitalopram, reboxetine, milnacipran, moclobemide and imipramine) or with MTEP led to significant increases in [(3)H]MPEP binding in homogenates of the hippocampus and/or cerebral cortex. Increases in mGlu5 expression were also observed, though they did not always parallel the increase in binding. The results indicate that adaptive up-regulation of mGlu5 receptors may be a common change induced by antidepressant drugs.
    Neuropharmacology 05/2014; DOI:10.1016/j.neuropharm.2014.04.016 · 4.82 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This review discusses case reports of patients treated with psychotropic medications for which therapeutic drug monitoring (TDM) was found useful. The use of this approach is based on the assumption that previous papers on TDM have largely used the available database of controlled studies to establish that excessively low concentrations of antidepressants, antipsychotics or mood stabilisers often lead to poor treatment response, whereas excessively high concentrations are associated with an increased risk of unwanted side effects and even poor response for some drugs. Typical situations in which TDM has been found to be clinically useful include poor compliance, patients who are ultra-rapid or poor metabolisers, elderly patients, instances of metabolic inhibition and induction, and patients with liver dysfunction. In order to provide clinically relevant information, certain practical aspects of TDM must be respected. The results of the assays must be rapidly available to the treating physician, selection of medications to be monitored must be based on the daily practice in the given psychiatric institution, analytical methods must be specific, and numerical results should be complemented by a short written comment. Under these conditions, TDM in psychiatry is a cost-effective means to assessing compliance, enhancing therapeutic response, avoiding toxicity, increasing quality of life and improving the therapeutic alliance.
    CNS Drugs 12/1995; 4(6). DOI:10.2165/00023210-199504060-00006 · 4.38 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A large number of drug interactions involving antidepressants have been described. Some of these are common to specific classes of antidepressant drugs, while others are related to peculiar properties of individual compounds and vary greatly from one compound to another within the same drug class. In general, the broader the range of receptors and enzymes affected by a given drug, the greater the potential for pharmacodynamic interactions. Older generation monoamine oxidase inhibitors (MAOIs) are particularly likely to cause interactions. These can occur with a wide range of compounds including tyra-mine-containing foods, alcohol (ethanol), opioids, sympathomimetic agents and other antidepressant drugs [e.g. tricyclic antidepressants (TCAs) and selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs)]. The more recently developed reversible and selective inhibitors of monoamine oxidase-A, such as moclobemide, appear to carry a much lower risk of causing serious drug interactions. TCAs affect several neurotransmitter systems, but to differing degrees. This may result in many clinically significant pharmacodynamic interactions, including the reversal of the hypotensive action of some centrally active antihypertensive agents and the potentiation of the effects of anticholinergic agents and CNS depressants. Important pharmacokinetic interactions with TCAs include induction of their metabolism by anticonvulsants and impairment of their elimination by metabolic inhibitors such as fluoxetine, fluvoxamine, antipsychotics and quinidine. Appropriate dosage adjustments may be required to minimise the potentially adverse effects resulting from these interactions. Some second generation antidepressants do not differ greatly from TCAs in pharmacological profile and so may be involved in similar interactions. However, others have a more selective mechanism of action and a lower potential for drug interactions. This is especially true for the SSRIs, which cause fewer pharmacodynamic interactions than MAOIs and TCAs. Nevertheless, SSRIs may interact adversely with drugs that also affect serotonergic transmission (including lithium) and may inhibit selectively the hepatic enzymes involved in the metabolism of concurrently prescribed drugs such as TCAs, antipsychotics, carbamazepine, oral anticoagulants and β-adrenoceptor blocking agents. Fluoxetine and paroxetine, in particular, appear to be powerful inhibitors of CYP2D6, whereas fluvoxamine is a more potent inhibitor of CYP1A2. Avoidance of unnecessary polytherapy, knowledge of the interaction potential of individual agents and careful individualisation of dosage based on close evaluation of clinical response are essential to minimise potentially adverse drug interactions among patients receiving antidepressant therapy.
    CNS Drugs 12/1994; 2(6). DOI:10.2165/00023210-199402060-00008 · 4.38 Impact Factor

Full-text (2 Sources)

Available from
May 27, 2014