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Clinical Pharmacokinetics

, Volume 18, Issue 5, pp 346–364 | Cite as

Clinical Pharmacokinetics of Imipramine and Desipramine

  • F. R. Sallee
  • B. G. Pollock
Drug Disposition

Summary

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.

Keywords

Imipramine Desipramine Debrisoquine Sparteine Cuna 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Abernethy DR, Divoll M, Greenblatt DJ, Harmatz JS, Shader RI. Absolute bioavailability of Imipramine: influence of food. Psychopharmacology 83: 104–106, 1984aCrossRefGoogle Scholar
  2. Abernethy DR, Greenblatt DJ, Shader RI. Imipramine-cimelidme interaction: impairment of clearance and enhanced absolute bioavailability. Journal of Pharmacology and Experimental Therapeutics 229: 702–705, 1984PubMedGoogle Scholar
  3. Abernethy DR, Greenblatt DJ, Shader RI. Imipramine and desipramine disposition in the elderly. Journal of Pharmacology and Experimental Therapeutics 232: 183–188, 1985PubMedGoogle Scholar
  4. Abernethy DR, Kerzner L. Age effects on alpha-1-acid glycoprotein concentration and Imipramine plasma protein binding. Journal of the American Geriatrics Society 32: 705–708, 1984PubMedGoogle Scholar
  5. Alexanderson B, Pharmacokinetics of desmethylimipraminc and nortriptyline in man after single and multiple oral doses. European Journal of Clinical Pharmacology 5: 1–10, 1972CrossRefGoogle Scholar
  6. Amsterdam J, Brunswick D, Mendels J. High dose desipraminc, plasma drug levels and clinical response. Journal of Clinical Psychiatry 40: 141–143, 1979PubMedGoogle Scholar
  7. Amsterdam JD, Brunswick DJ, Potter L, Kaplan MJ. Cimetidineinduced alterations in desipramine plasma concentrations. Psychopharmacology 83: 373–375. 1984PubMedCrossRefGoogle Scholar
  8. Amsterdam JD, Brunswick DJ, Potter L, Winokur A, Rickeis K, Desipramine and 2-hydroxydesipramine plasma levels in endogenous depressed patients. Archives of General Psychiatry 42: 361–364, 1985PubMedCrossRefGoogle Scholar
  9. 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
  10. Arias TD, Jorge LF, Inaba T. No evidence for the presence of poor metabolizers of sparteine in an Amerindian group: the Cunas of Panama. British Journal of Clinical Pharmacology 21: 547–549, 1986PubMedCrossRefGoogle Scholar
  11. 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
  12. Baldessarini RJ, Teicher MH, Cassidy JW, et al. Anticonvulsant cotreatmenl may increase toxic metabolites of antidepressants and other psychotropic drugs. Journal of Clinical Psyehopharmacology 8: 381, 1988CrossRefGoogle Scholar
  13. Baumann P, Tinguely D, Schopf J. Increase of α1-acid glycoprotein after treatment with amitriptyline. British Journal of Clinical Pharmacology 14: 102–103, 1982PubMedCrossRefGoogle Scholar
  14. Beckelt AH, Al-Sarraj S, Metabolism of amitriptyline, nortripyline, Imipramine and desipramine to yield hydroxylamincs. Journal of Pharmacy and Pharmacology 25: 335–336, 1973CrossRefGoogle Scholar
  15. Bell IR, Cole JO, Fluoxetinc induces elevation of desipramine level and exacerbation of geriatric non-psychotic depression. Journal of Clinical Psyehopharmacology 8: 447–448, 1988CrossRefGoogle Scholar
  16. Bertilsson L, Aberg-Wistedt A. The debnsoquine hydroxylation test predicts steady-stale plasma levels of desipramine. British Journal of Clinical Pharmacology 15: 388–390, 1983PubMedCrossRefGoogle Scholar
  17. Bertschy G, Vandel S, Vandel B, Allers G, Bechtcl P, et al. Desipramine dose prediction based on 24-hour single-dose levels: feasibility and validity. Pharmacopsychiatry 22: 161–164, 1989PubMedCrossRefGoogle Scholar
  18. Bickel MH, Binding of chlorpromazine and imipramine to red cells, albumin, lipoproteins and other blood components. Journal of Pharmacy and Pharmacology 27: 733–738. 1975PubMedCrossRefGoogle Scholar
  19. Bickel MH, Graber BE, Moor M, Distribution of chlorpromazine and imipramine in adipose and other tissues of rats. Life Sciences 33: 2025–2031, 1983PubMedCrossRefGoogle Scholar
  20. Bickel MH, Weder HJ, Demethylation of imipramine in the rat as influenced by SKF 525 A and by different routes of administration. Life Sciences 7: 1223–1230, 1968PubMedCrossRefGoogle Scholar
  21. Birgersson C, Morgan ET, Jornvall H, von Bahr C, Purification of a desmethylimipraminc and debrisoquine hydroxylating cytochrome p-450 from human liver. Biochemical Pharmacology 35: 3165–3166, 1986PubMedCrossRefGoogle Scholar
  22. Bjerre M, Gram LF, Kragh-Sorensen P, Kristensen CB, Pedcrsen OL, et al. Dose-dependent kinetics of imipramine in elderly patients. Psyehopharmacology 75: 354–357, 1981CrossRefGoogle Scholar
  23. Bock JL, Nelson JC, Gray S, Jatlow PI. Desipramine hydroxylation: variability and effect of anlipsychotic drugs. Clinical Pharmacology and Therapeutics 33: 322–328, 1983PubMedCrossRefGoogle Scholar
  24. 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
  25. Brøsen K, Gram LF, First-pass metabolism of Imipramine an ddesipramine: impact of the sparteine oxidation phenotype. Clinical Pharmacology and Therapeutics 43: 400–406, 1988PubMedCrossRefGoogle Scholar
  26. Brøsen K, Gram LF, Klysner R, Bech P. Steady-state levels of Imipramine and us metabolites: significance of dose-dependent kinetics. European Journal of Clinical Pharmacology 30: 43–49, 1986bPubMedCrossRefGoogle Scholar
  27. Brøsen K, Gram LF, Klysner R, Otton SV, Bech P. et al. Steadystate concentrations of imipramine and its metabolites in relation to the sparteine/debrisoquine polymorphism. European Journal of Clinical Pharmacology 30: 679–684, 1986aPubMedCrossRefGoogle Scholar
  28. Brøsen K. Otton SV, Gram LF, Imipramine demethylation and hydroxylation: impact of the sparteine oxidation phenotype. Clinical Pharmacology and Therapeutics 40: 543–549, 1986cPubMedCrossRefGoogle Scholar
  29. Brunswick DJ, Amsterdam JD, Mendels J, Stern SL, Prediction of steady-state Imipramine and desmethylimipramine plasma concentrations from single dose data. Clinical Pharmacology and Therapeutics 25: 605–610, 1979PubMedGoogle Scholar
  30. Burckhardt D, Raeder E, Muller V, Imhof P, Neubauer H. Cardiovascular effects of tricyclic and tetracyclic antidepressants. Journal of the American Medical Association 239: 213–216, 1978PubMedCrossRefGoogle Scholar
  31. Christiansen J, Gram LF, Imipramine and its metabolites in human brain. Journal of Pharmacy and Pharmacology 25: 604–608, 1973PubMedCrossRefGoogle Scholar
  32. Christiansen J, Gram LF, Kofod B, Rafaelsen OJ. Imipramine metabolism in man. Psychopharmacologia 11: 255–264, 1967PubMedCrossRefGoogle Scholar
  33. Ciraulo DA, Alderson LM, Chaproon DJ, Jaffe JH, Bollepalli S, et al. Imipramine disposition in alcoholics. Journal of Clinical Psyehopharmacology 2: 2–7, 1982CrossRefGoogle Scholar
  34. Ciraulo DA, Barnhill JG, Jaffe JH. Clinical pharmacokinetics of imipramine and desipramine in alcoholics and normal volunteers. Clinical Pharmacology and Therapeutics 43: 509–518, 1988PubMedCrossRefGoogle Scholar
  35. Cole JO, Where are those new antidepressants we were promised? Archives of General Psychiatry 45: 193–194, 1988PubMedCrossRefGoogle Scholar
  36. Cooke RG, Warsh JJ, Stancer HC, Reed KL, Persad E. The nonlinear kinetics of desipramine and 2-hydroxydesipramine in plasma. Clinical Pharmacology and Therapeutics 36: 343–349, 1984PubMedCrossRefGoogle Scholar
  37. Cooper TB, Bark N, Simpson GM, Prediction of steady state plasma and saliva levels of desmethylimipramine using a single dose, single time point procedure. Psyehopharmacology 74: 115–121, 1981CrossRefGoogle Scholar
  38. Costa D, Predescu V, Visan-Ionescu I, Ciurezu T, Endogenous depression and imipramine levels in the blood. Psychopharmacology 70: 291–294, 1980PubMedCrossRefGoogle Scholar
  39. Crammer SL, Scott B, Rolfe B, Metabolism of 14C-imipramine: II. Urinary metabolites in man. Psychopharmacologia 15: 207–225, 1969PubMedGoogle Scholar
  40. Cutler NR, Zavadil AP, Eisdorfer G, Ross RJ, Potter WZ, Concentrations of desipramine in elderly women are not elevated. American Journal of Psychiatry 138: 1235–1237, 1981PubMedGoogle Scholar
  41. Danon A, Chen Z, Binding of imipramine to plasma proteins: effect of hyperlipoproteinemia. Clinical Pharmacology and Therapeutics 25: 316–321, 1979PubMedGoogle Scholar
  42. 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
  43. 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
  44. Devane CL, Cyclic antidepressants. In Evans et al (Eds) Applied pharmacokinetics: principles of therapeutic drug monitoring, pp. 549–585, Applied Therapeutics. Spokane, 1980Google Scholar
  45. Devane CL, Jusko WJ. Plasma concentrations monitoring of hydroxylated metabolites of imipramine and desipramine. Drug Intelligence and Clinical Pharmacy 15: 263–266, 1981PubMedGoogle Scholar
  46. Devane CL, Savelt M, Jusko WJ, Desipramine and 2-hydroxy desipramine pharmacokinetics in normal volunteers. European Journal of Clinical Pharmacology 19: 61–64, 1981PubMedCrossRefGoogle Scholar
  47. Distlerath LM, Guengench FP. Characterization of a human liver cytochrome P-450 involved in the oxidation of debrisoquin and other drugs by using antibodies raised to the analogous rat enzyme. Proceedings of the National Academy of Sciences USA 81: 7348–7352, 1984CrossRefGoogle Scholar
  48. Dugas JE, Bishop DS, Nonlinear desipramine pharmacokinetics: a case study. Journal of Clinical Psychopharmacology 5: 43–45, 1985PubMedCrossRefGoogle Scholar
  49. Eichelbaum M, Defective oxidation of drugs: pharmacokinctic and therapeutic implications. Clinical Pharmacokinetics 7: 1–22, 1982PubMedCrossRefGoogle Scholar
  50. Eichelbaum M, Spannbrucker N, Steincke B, Dengler HJ, Defective N-oxidation of spaneine in man: a new pharmacogenetic defect. European Journal of Clinical Pharmacology 16: 183–187, 1979PubMedCrossRefGoogle Scholar
  51. Eichelbaum M, Woolhouse NM. Inter-ethnic difference in sparteine oxidation among Ghanaians and Germans. European Journal of Clinical Pharmacology 28: 79–83, 1985PubMedCrossRefGoogle Scholar
  52. El-Fakahany E, Richelson E. Antagonism by antidepressants of muscarinic acetylcholine receptors of human brain. British Journal of Pharmacology 78: 97–102, 1983PubMedGoogle Scholar
  53. 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
  54. Freilich DI, Giardina EV. Imipramine binding to alpha-1-acid glycoprotein in normal subjects and cardiac patients. Clinical Pharmacology and Therapeutics 35: 670–674, 1984PubMedCrossRefGoogle Scholar
  55. Glassman AH, Hurwic MJ, Perel JM. Plasma binding of Imipramine and clinical outcome. American Journal of Psychiatry 130: 1367–1369, 1973PubMedGoogle Scholar
  56. Glassman AH, Johnson LL, Giardina E-G, Walsh BT, Roose SP. The use of imipramine in depressed patients with congestive heart failure. Journal of the American Medical Association 250: 1997–2001, 1983PubMedCrossRefGoogle Scholar
  57. Glassman AH, Perel JM, Shostak M, Kantor S, Fleiss JL. Clinical implications of Imipramine plasma levels for depressive illness. Archives of General Psychiatry 34: 197–204, 1977PubMedCrossRefGoogle Scholar
  58. 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
  59. Gonzalez FJ, Skoda RC, Kimura S, Umeno M, Zanger UM, et al. Characterization of the common genetic defect in humans deficient in debrisoquine metabolism. Nature 331: 442–446, 1988PubMedCrossRefGoogle Scholar
  60. Gram LF, Andreasen PB, Overo KF, Christiansen J. Comparison of single dose kinetics of imipramine, nortriptyline, and antipyrine in man. Psychopharmacology Bulletin 50: 21–27, 1976CrossRefGoogle Scholar
  61. Gram LF, Bjerre M. Kragh-Sorensen P. Kvinesdal B, Molin J, et al. Imipramine metabolics in blood of patients during therapy and after overdose. Clinical Pharmacology and Therapeutics 33: 335–343. 1983PubMedCrossRefGoogle Scholar
  62. Gram LF, Christiansen J, First-pass metabolism of imipramine in man. Clinical Pharmacology and Therapeutics 17: 555–563. 1975PubMedGoogle Scholar
  63. Gram LF, Kofod B, Christiansen J. Rafaelsen OJ. Imipraminc metabolism: pH-dependent distribution and urinary excretion. Clinical Pharmacology and Therapeutics 12: 239–244, 1971PubMedGoogle Scholar
  64. Gram LF, Overo KF. Drug interaction: inhibitory effects of neuroleptics on metabolism of tricyclic antidepressants in man. British Medical Journal 163: 463–465. 1972CrossRefGoogle Scholar
  65. Gram LF, Sondergaad IB, Christiansen J. Petersen GO, Bech P. et al. Steady-state kinetics of imipramine in patients. Psychopharmacology 54: 255–261. 1977PubMedCrossRefGoogle Scholar
  66. Greenblatt DJ. The pharmacokinetization of psychiatry. Journal of Clinical Pharmacology 25: 239–240. 1985PubMedGoogle Scholar
  67. Greenblatt DJ, Sellers EM. Koch-Weser J. Importance of protein binding for the interpretation of serum or plasma drug concentrations. Journal of Clinical Pharmacology 22: 259–263. 1982PubMedGoogle Scholar
  68. Hammer W, Sjoqvist F. Plasma levels of monomethylaled tricyclic antidepressants during treatment with imipramine-like compounds. Life Sciences 6: 1895–1903, 1967PubMedCrossRefGoogle Scholar
  69. 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
  70. Inaba T, Jurima M, Nakano M, Kalow W, Mephenytoin and spaneine pharmacogenetics in Canadian Caucasians. Clinical Pharmacology and Therapeutics 36: 670–676, 1984PubMedCrossRefGoogle Scholar
  71. Jandhyala B, Steenberg M, Perel JM, Manian AA, Buckley J, Effects of several tricyclic antidepressants on the hemodynamics and myocardial contractility of anesthetized dogs. European Journal of Pharmacology 42: 403–410, 1977PubMedCrossRefGoogle Scholar
  72. Javaid JI, Perel J, Davis JM, Inhibition of biogenic amines uptake by imipramine, desipramine. 2-OH-imipramine and 2-OH-desipramine in rat brain. Life Sciences 24: 21–28, 1979PubMedCrossRefGoogle Scholar
  73. Jorgensen OS, Lober M, Christiansen J, Gram LF, Plasma concentration and clinical effect in imipramine treatment of childhood enuresis. Clinical Pharmacokinetics 5: 386–393. 1980PubMedCrossRefGoogle Scholar
  74. Jusko WJ, Influence of cigarette smoking on drug metabolism in man. Drug Metabolism Review 9: 221–228, 1979CrossRefGoogle Scholar
  75. 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
  76. Kocsis JH, Hanin I, Bowden C, Brunswick D. Imipramine and amitriptyline plasma concentrations and clinical response in major depression. British Journal of Psychiatry 148: 52–57, 1986PubMedCrossRefGoogle Scholar
  77. Kragh-Sorensen P, Larson NE, Factors influencing nortriptyline steady-state kinetics. Clinical Pharmacology and Therapeutics 28: 796–803, 1986Google Scholar
  78. Kristensen CB, Imipramine serum protein binding in health subjects. Clinical Pharmacology and Therapeutics 34: 689–694, 1983PubMedCrossRefGoogle Scholar
  79. Kruger R, Holzl G, Kuss HJ, Schefold L. Comparison of the metabolism of the three antidepressants amitriptyline, imipramine, and chlorimipramine in vitro in rat liver microsomes. Psychopharmacology 88: 505–513, 1986PubMedCrossRefGoogle Scholar
  80. Kuhn R, Untersuchungen uber mogliche Zusammenhange zwischen Metabolitenausscheidung and Krankheitsverlauf depressive zustande unter Imipramin-Medikation. Psychopharmacologia 8: 201–222, 1965PubMedCrossRefGoogle Scholar
  81. Kutcher SP, Reid K, Dubbin JD, et al. Electrocardiogram changes and therapeutic desipramine and 2-hydroxy-desipramine concentrations in elderly depressives. British Journal of Psychiatry 148: 676–679, 1986PubMedCrossRefGoogle Scholar
  82. Lake CR, Mikkelsen EJ, Rapoport JL, Zavadil III AP, Kopin IJ. Effects of imipramine and norepinephrine and blood pressure in enuretic boys. Clinical Pharmacology and Therapeutics 26: 647–653, 1979PubMedGoogle Scholar
  83. Lieberman JA, Cooper TB, Suckow RF, Steinberg H, Borenstein M, et al. Tricyclic antidepressant levels in chronic renal failure. Clinical Pharmacology and Therapeutics 37: 301–307, 1985PubMedCrossRefGoogle Scholar
  84. Linnoila M, Dorrity F, Jobson K. Plasma and erythrocyte levels of tricyclic antidepressants in depressed patients. American Journal of Psychiatry 135: 557–561, 1978PubMedGoogle Scholar
  85. Mahgoub A, Idle JR, Dring LG, Lancaster R, Smith RL. Polymorphic hydroxylation of debrisoquine in man. Lancet 2: 584–586, 1977PubMedCrossRefGoogle Scholar
  86. Mellstrom B, Bertilsson L, Lou Y-C, Sawe J, Sjoqvist F. Amitriptyline metabolism: relationship to polymorphic debrisoquine hydroxylation. Clinical Pharmacology and Therapeutics 34: 516–520, 1983PubMedCrossRefGoogle Scholar
  87. Meilstrom B, Bertilsson L, Sawe J, Schulz HU, Sjoqvist F. E-and Z-10-hydroxylation of nortriptyline: relationship to polymorphic debrisoquine hydroxylation. Clinical Pharmacology and Therapeutics 30: 189–193, 1981CrossRefGoogle Scholar
  88. Meilstrom B, Sawe J, Berlilsson L, Sjoqvist F. Amitriptyline mclabolism: association with dcbrisoquine hydroxylation in nonsmokers. Clinical Pharmacology and Therapeutics 39: 369–371, 1986CrossRefGoogle Scholar
  89. Moody JP, Tait AC, Todrick A. Plasma levels of imipramine and desmcthylimipraminc during therapy. British Journal of Psychiatry 133: 183–193, 1967CrossRefGoogle Scholar
  90. Musccttola G, Goodwin FK, Potter WZ, Claeys MM, Markey SP. Imipramine and desipramine in plasma and spinal fluid: relationship to clinical response and serotonin metabolism. Archives of General Psychiatry 35: 621–625, 1978CrossRefGoogle Scholar
  91. Nagy A, Johansson R, Plasma levels of Imipramine and desipramine in man after different routes of administration. Naunvn-Schmiedeberg’s Archives of Pharmacology 290: 145–160, 1975CrossRefGoogle Scholar
  92. Nagy A, Johansson R, The demcthylation of Imipramine and clomipramine as apparent from their plasma kinetics. Psychopharmacology 54: 125–131, 1977PubMedCrossRefGoogle Scholar
  93. Nagy A, Treiber L. Quantitative determination of imipramine and desipramine in human blood plasma by direct densitometry of thinlayer chromatograms. Journal of Pharmacy and Pharmacology 25: 599–603, 1973PubMedCrossRefGoogle Scholar
  94. Nakamura K, Goto F, Ray A, et al. Interelhnic differences in genetic polymorphism of debrisoquine and mephenytoin hydroxylation between Japanese and Caucasian populations. Clinical Pharmacology and Therapeutics 38: 402–408, 1985PubMedCrossRefGoogle Scholar
  95. Nakano S, Hollister LE, Chronopharmacology of amitriptyline. Clinical Pharmacology and Therapeutics 33: 453–459, 1982Google Scholar
  96. Nelson JC, Atillasoy E, Mazure C, Jatlow PI, Hvdroxvdesipramine in the elderly. Journal of Clinical Psychopharmacology 8: 428–433, 1988bPubMedCrossRefGoogle Scholar
  97. Nelson JC, Jatlow P, Nonlinear desipramine kinetics: prevalence and importance. Clinical Pharmacology and Therapeutics 41: 666–670, 1987PubMedCrossRefGoogle Scholar
  98. Nelson JC, Jatlow PI, Mazure C, Desipramine plasma levels and response in elderly melancholic patients. Journal of Clinical Psychopharmacology 5: 217–220, 1985PubMedCrossRefGoogle Scholar
  99. Nelson JC, Jatlow P, Quinlan DM, et al. Desipramine plasma concentration and anlidcpressanl respones. Archives of General Psychiatry 39: 1419–1422, 1982PubMedCrossRefGoogle Scholar
  100. Nelson JC, Mazure C, Jatlow PI, Antidepressanl activity of 2-hydroxydesipramine. Clinical Pharmacology and Therapeutics 44: 283–288, 1988aPubMedCrossRefGoogle Scholar
  101. Nies A, Robinson DS, Friedman MJ, Green R, Cooper TB, et al. Relationship between age and tricyclic antidepressant plasma levels. American Journal of Psychiatry 134: 790–793, 1977PubMedGoogle Scholar
  102. Nordin C, Siwers B, Bcnitez J, Bertilsson L, Plasma concentrations of nortriptyline and its 10-hydroxy metabolite in depressed patients — relationship to the debnsoquine hydroxylation metabolic ratio. British Journal of Clinical Pharmacology 19: 832–835, 1985PubMedCrossRefGoogle Scholar
  103. Osikowska-Evers B, Dayer P, Meyer UA, Robertz GF, Eichelbaum M, Evidence for altered catalytic properties of the cylochrome P-450 involved in the spartcine oxidation in poor metabolizers. Clinical Pharmacology and Therapeutics 41: 320–325, 1987PubMedCrossRefGoogle Scholar
  104. Otton SV, Inaba T, Kalow W, Inhibition of sparteine oxidation in human liver by Iricyclic antidepressants and other drugs. Life Sciences 32: 795–800, 1983PubMedCrossRefGoogle Scholar
  105. Pearl GF, Boutagy J, Shenfield GM, Dcbnsoquin oxidation in an Australian population. British Journal of Clinical Pharmacology 21: 465–471, 1986CrossRefGoogle Scholar
  106. 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
  107. Perel JM, Stiller RL, Glassman AH, Studies on plasma level/effect relationships in Imipramine therapy. Communications in Psychopharmacology 2: 429–439, 1978bPubMedGoogle Scholar
  108. Perry PJ, Pfohl BM, Holstad SG, The relationship between antidepressant response and tricyclic antidepressant plasma concentrations: retrospective analysis of the literature using logistic regression analysis. Clinical Pharmacokinetics 13: 381–392, 1987PubMedCrossRefGoogle Scholar
  109. Piafsky KM, Borga O, Plasma protein of basic drugs II: importance of alpha-l acid glycoprotein for interindividual variation. Clinical Pharmacology and Therapeutics 22: 545–549, 1977PubMedGoogle Scholar
  110. Pollock BG, Perel JM, Hydroxymetabolites of iricyclic antidepressants: evaluation for relative cardiotoxicity. In Dahl & Gram (Eds) Clinical pharmacology in psychiatry: molecular studies to clinical reality, pp 232–236, Springer-Verlag, Berlin. 1989CrossRefGoogle Scholar
  111. 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
  112. Potter WZ, Cahl HM, Manian AA, Zavadil AP, Goodwin FK, Hydroxylated metabolites of tricyclic antidepressants: preclinical assessment of activity. Biological Psychiatry 14: 601–613, 1979bPubMedGoogle Scholar
  113. Potter WZ, Calil HM, Sutfin TA, Zavadil AP, Jusko WJ, et al. Active metabolites of imipramine and desipramine in man. Clinical Pharmacology and Therapeutics 31: 393–401, 1982PubMedCrossRefGoogle Scholar
  114. 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
  115. Potter WZ, Muscetlola G, Goodwin FK, Binding of imipramine 10 plasma protein and to brain tissue: relationship to CSF tricyclic levels in man. Psychopharmacology 63: 187–192, 1979aPubMedCrossRefGoogle Scholar
  116. Potter WZ, Zavadil AP, Kopin IJ, Goodwin FK, Single-dose kinetics predict steady-slate concentrations of imipramine and desipramine. Archives of General Psychiatry 37: 314–320, 1980bPubMedCrossRefGoogle Scholar
  117. Preskorn SH, Bupp SJ, Weller EB, Weller RA. Plasma levels of Imipramine and metabolites in 68 hospitalized children. Journal of the American Academy of Child and Adolescent Psychiatry 28: 373–375, 1989PubMedCrossRefGoogle Scholar
  118. Preskorn SH, Jerkovich GS, Hughes C, Weller R, Depression in children: concentration dependent CNS toxicity of tricyclic antidepressants. Psychopharmacology Bulletin 24: 275–279, 1988PubMedGoogle Scholar
  119. Preskorn SH, Weiler EB, Hughes CW, Weller RA. Relationship of plasma imipramine levels to CNS toxicity in children. American Journal of Psychiatry 145: 897, 1988PubMedGoogle Scholar
  120. Price-Evans DA, Harmer D, Downham DY, Whibley EJ, Idle JR, et al. The genetic control of sparteine and debrisoquin metabolism in man with new methods of analysing bimodal distributions. Journal of Medical Genetics 20:321–329, 1983CrossRefGoogle Scholar
  121. Price-Evans DA, Mahgoub A, Sloan TP, Idle JR, Smith RL, A family and population study of the genetic polymorphism of debrisoquine in a while British population. Journal of Medical Genetics 17: 102–105, 1980CrossRefGoogle Scholar
  122. Reidenberg MM, Odar-Cedcrlof I, von Bahr C, Borga O, Sjoqvist F, Protein binding of diphenylhydantoin and desmcthylimipraminc in plasma from patients with poor renal function. New England Journal of Medicine 285: 264–267, 1971PubMedCrossRefGoogle Scholar
  123. Rigal JG, Albin H, Duchier AR, D’Aulnay, JM, Fenelon JH, el al, Imipramine blood levels and clinical outcome, Journal of Clinical Psychopharmacology 7: 222–229, 1987PubMedCrossRefGoogle Scholar
  124. 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
  125. Rudorfer MV, Lane, Potter WZ, Interelhnic dissociation between debrisoquin and desipramine hydroxylation. Journal of Clinical Psychopharmacology 5: 89–92, 1985PubMedCrossRefGoogle Scholar
  126. Sallee F, Stiller R, Perel J, Rancurello M, Targeting Imipramine dose in children with depression. Clinical Pharmacology and Therapeutics 40: 8–13, 1986PubMedCrossRefGoogle Scholar
  127. Sathananthan GL, Gershon S, Almeida M, Spector S, Correlation between plasma and cerebrospinal levels of Imipramine. Archives of General Psychiatry 33: 1109–1110, 1976PubMedCrossRefGoogle Scholar
  128. Schindler W, Uber die Konstitutionsermittlung and Synthese eines Metaboliten von N-(lmethylaminopropyl)-iminodibenzyl-hydrochlorid. Helvetica Chimica Acta 43: 35–42, 1960CrossRefGoogle Scholar
  129. Sigg EG, Osborne M, Korol B, Cardiovascular effects of imipramine. Journal of Pharmacology and Experimental Therapeutics 141: 237–243, 1963PubMedGoogle Scholar
  130. Sjoqvist F, Berglund F, Borga O, Hammer W, Andersson S, et al. The pH-dependent excretion of monomethylated tricyclic antidepressants in dog and man. Clinical Pharmacology and Therapeutics 10: 826–833, 1969PubMedGoogle Scholar
  131. Slattery JT, Gibaldi M, Koup JR. Prediction of maintenance dose required to attain a desired drug concentration at steady-state from a single determination of concentration after an initial dose. Clinical Pharmacokinetics 5: 377–385, 1980PubMedCrossRefGoogle Scholar
  132. Spina E, Birgersson C, von Bahr C, Ericsson O, Mellstrom B, et al. Phenotypic consistency in hydroxylation of dcsmethylimipramine and debrisoquine in healthy subjects and in human liver microsomes. Clinical Pharmacology and Therapeutics 36: 677–682, 1984PubMedCrossRefGoogle Scholar
  133. Spina E, Henthorn T, Eleborg L, Desmethylimipramine overdose: nonlinear kinetics in a slow hydroxylator. Therapeutic Drug Monitoring 5: 239–241, 1985CrossRefGoogle Scholar
  134. Spina E, Koike Y, Differential effects of Cimetidine and ranitidine on Imipramine demethylation and desmethylimipramine hydroxylation by human liver microsomes. European Journal of Clinical Pharmacology 30: 239–242, 1986PubMedCrossRefGoogle Scholar
  135. Spina E, Pacifici GM, von Bahr C, Rane A. Characterization of desmethylimipramine 2-hydroxylation in human foetal and adult liver microsomes. Acta Pharmacologica et Toxicologica 58: 277–281, 1986PubMedCrossRefGoogle Scholar
  136. Spina E, Steiner E, Orjan E, et al. Hydroxylation of desmethylimipramine: dependence on the debrisoquin hydroxylation phenotype. Clinical Pharmacology and Therapeutics 41: 314–319, 1987PubMedCrossRefGoogle Scholar
  137. Steiner E, Iselius L, Alvan G, Lindsten J, Sjöqvist FA, A family study of genetic and environmental factors determining polymorphic hydroxylation of debrisoquin in man. Clinical Pharmacology and Therapeutics 38: 394–401, 1985PubMedCrossRefGoogle Scholar
  138. Stout SA, DeVane CL, Quantification of Imipramine and its major metabolites in whole blood, brain, and other tissues of the rat by liquid chromatography. Psychopharmacology 84: 39–41, 1984PubMedCrossRefGoogle Scholar
  139. Sulser F, Watts J, Brodie BB. On the mechanism of antidepressant action of imipramine-like drugs. Annals of the New York Academy of Science 96: 279–286, 1962CrossRefGoogle Scholar
  140. Sutfin TA, Devane CL, Jusko WJ. The analysis and disposition of imipramine and its active metabolites in man. Psychopharmacology 82: 310–317, 1984PubMedCrossRefGoogle Scholar
  141. Sutfin TA, Perini Gl, Molnar G, Jusko WJ, Multiple-dose pharmacokinetics of imipramine and its major active and conjugated metabolites in depressed patients. Journal of Clinical Psychopharmacology 8: 48–53, 1988PubMedCrossRefGoogle Scholar
  142. Tollefson G, Valentine R, Garvey M, Tuanson VB, Imipramine metabolism in recurrent depressive episodes. Journal of Affective Disorders 8: 183–186, 1985PubMedCrossRefGoogle Scholar
  143. Vinks A, Inaba T, Otton SV, Kalow W, Sparteine metabolism in Canadian Caucasians. Clinical Pharmacology and Therapeutics 31: 23–29, 1982PubMedCrossRefGoogle Scholar
  144. von Bahr C, Spina E, Birgerson C, Ericsson O, Goransson M, et al. Inhibition of desmethylimipramine 2-hydroxylation by drugs in human liver microsomes. Biochemical Pharmacology 34: 2501–2505, 1985CrossRefGoogle Scholar
  145. Weiler EB, Weller RA, Preskorn SH, Steady-state plasma imipramine levels in prepubertal depressed children. American Journal of Psychiatry 139: 506–508, 1982Google Scholar
  146. Wilkerson RD, Antiarrhythmic effects of tricyclic antidepressant drugs in ouabain-induced arrhythmias in the dog. Journal of Pharmacology and Experimental Therapeutics 205: 666–674, 1978PubMedGoogle Scholar
  147. Wilkinson GR, Shand DG, A physiological approach to hepatic drug clearance. Clinical Pharmacology and Therapeutics 18: 377–390, 1975PubMedGoogle Scholar
  148. Woolhouse NM, Adjepon-Yamoah KK, Mellstrom B, Hedman A, Bertilsson L, et al. Nortriptyline and debrisoquin hydroxylation in Ghanaian and Swedish subjects. Clinical Pharmacology and Therapeutics 36: 374–378, 1984PubMedCrossRefGoogle Scholar
  149. Zeidenberg P, Perel JM, Kanzler M, Warthon RN, Malitz S, Clinical and metabolic studies with imipramine in man. American Journal of Psychiatry 127: 1321–1326, 1971PubMedGoogle Scholar

Copyright information

© ADIS Press Limited 1990

Authors and Affiliations

  • F. R. Sallee
    • 1
    • 2
  • B. G. Pollock
    • 1
    • 2
  1. 1.Department of PsychiatryMedical University of South CarolinaCharlestonUSA
  2. 2.University of PittsburghPittsburghUSA

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