Clinical Pharmacokinetics of Imipramine and Desipramine
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The pharmacokinetics of Imipramine and desipramine have been extensively investigated with recent studies designed to understand sources of intersubject variability and to study discrete clinical populations rather than healthy volunteers. Sources of intersubject variability in pharmacokinetics are both genetic (oxidative phenotype) and environmental. Oxidative phenotype has an important impact on first-pass metabolism. In individuals with poor metabolism, systemic availability for imipramine is increased. Intrinsic clearance of desipramine is reduced 4-fold in individuals with poor metabolism.
Recent pharmacokinetic studies in diverse patient populations such as the depressed elderly, children and alcoholics have revealed decreased clearance of imipramine in the elderly and increased clearance of both imipramine and desipramine in chronic alcoholics. In at least a third of the population, nonlinear pharmacokinetics of desipramine may be observed at steady-state plasma concentrations above 150 μg/L. These nonlinear changes in desipramine pharmacokinetics are not associated with age or sex, but are associated with higher desipramine 2-hydroxydesipramine concentration ratios. Hydroxylated metabolites of imipramine and desipramine may posses both antidepressants and cardiotoxic activity but their formation is rate limited and plasma concentrations tend to follow the parent compound with little accumulation. The potent cardiovascular effects of the hydroxymetabolites may be particularly relevant for the elderly and in acute overdose.
KeywordsImipramine Desipramine Debrisoquine Sparteine Cuna
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- Antal EJ, Lawson IR, Aldcrson LM, Chapron DJ, Kramer PA. Estimating steady slate desipramine levels in noninstitutionalized elderly patients using single dose disposition parameters. Journal of Clinical Psyehopharmacology 2: 193–198, 1982Google Scholar
- Balant-Gorgia AE, Baient LP, Genet Ch, Dayer P, Aeschlimann JM, et al. Importance of oxidative polymorphism and Icvomepromazine treatment on the steady-state blood concentrations of clomipramine and its major metabolics. European Journal of Clinical Pharmacology 31: 449–455. 1986PubMedCrossRefGoogle Scholar
- Brinkschultc M, Brcser-Plaff U, The role of lipoproteins in the binding of tricyclic antidepressants and perazine to human plasma. In Usdin et al. (Eds) Phenothiazines and structurally related drugs, pp. 189–192, Elsevier, Amsterdam, 1980Google Scholar
- Dayton PG, Israili ZH, Cunningham RF, Stiller R, Perel JM. The effects of lipids on the binding of imipramine and other drugs to serum proteins. In Usdin et al. (Eds) Phenothiazines and structurally related drugs, pp. 185–188, Elsevier. Amsterdam. 1980Google Scholar
- Dencker H, Dencker SJ, Green A, Nagy A. Intestinal absorption, demethylation, and enterohepatic circulation of imipramine. Clinical Pharmacology and Therapeutics 15: 584–586, 1976Google Scholar
- Devane CL, Cyclic antidepressants. In Evans et al (Eds) Applied pharmacokinetics: principles of therapeutic drug monitoring, pp. 549–585, Applied Therapeutics. Spokane, 1980Google Scholar
- Ereshefskey L, Tran-Johnson T, Davis CM, LeRoy A. Pharmacokinetic factors affecting antidepressant drug clearance and clinical effect: evaluation of doxepin and Imipramine. Clinical Chemistry 34: 863–880, 1988Google Scholar
- Glassman AH, Roose SP, Giardina E-G, Bigger JT. Cardiovascular effects of tricyclic antidepressants. In Meltzer (Ed.) Psychopharmacology: the third generation of progress. Raven Press, New York, pp 1437–1442, 1987Google Scholar
- Heikkila RE, Goldfinger SS, Orlansky H, The effect of various phenothiazines and tricyclic antidepressants on the accumulation and release of (3H)norepinephnne and (3H)5-hydroxytryptamine in slices of rat occipital cortex. Research Communications in Chemical Pathology and Pharmacology 13: 237–250, 1976PubMedGoogle Scholar
- Kitanaka I, Ross RJ, Cutler NR, Zavadil AP, Potter WZ. Altered hydroxydesipramine concentrations in elderly depressed patients. Clinical Pharmacology and Therapeutics 18: 517–520, 1982Google Scholar
- Kragh-Sorensen P, Larson NE, Factors influencing nortriptyline steady-state kinetics. Clinical Pharmacology and Therapeutics 28: 796–803, 1986Google Scholar
- Nakano S, Hollister LE, Chronopharmacology of amitriptyline. Clinical Pharmacology and Therapeutics 33: 453–459, 1982Google Scholar
- Perel JM, Irani F, Hurivic M, Classman AH, Manian AA, Tricvclic antidepressants: relationships among pharmacokinctics, metabolism and clinical oulcome. In Garattini (Eds) Depressive disorders, pp. 325–336, FK Schallauer Verlag. Stuttgart. 1978aGoogle Scholar
- Pollock BG, Perel JM, Stiller RL, Birder LA, Manian AA, Comparative cardiotoxicity and pharmacokinetics of imipramine and 2-hydroxvimipramine in unanesthetized swine. Clinical Research 35: 380, 1987Google Scholar
- Potter WZ, Calil HM, Zavadil AP, Steady-state concentrations of hydroxylated metabolites of tricyclic antidepressants in patients: relationship to clinical effect. Psychopharmacology Bulletin 16: 32–34, 1980aGoogle Scholar
- Rubinstein G, McIntyre I, Burrows GD, Norman TR, Maguire KP. Metabolism of tricyclic antidepressant drugs. In Burrows et al. (Eds) Anlidepressants. pp. 57–74, Elsevier. Amsterdam. 1983Google Scholar
- Weiler EB, Weller RA, Preskorn SH, Steady-state plasma imipramine levels in prepubertal depressed children. American Journal of Psychiatry 139: 506–508, 1982Google Scholar