Psychopharmacology

, Volume 74, Issue 2, pp 115–121 | Cite as

Prediction of steady state plasma and saliva levels of desmethylimipramine using a single dose, single time point procedure

  • Thomas B. Cooper
  • Nigel Bark
  • George M. Simpson
Original Investigations

Abstract

In normal volunteer study (20 subjects) where each ingested 75 mg desmethylimipramine (DMI), blood and saliva samples were collected at 1, 2, 3, 4, 5, 7, 12, 24, and 32 h post dose. Each subject then was given DMI 25 mg b.i.d. for 15 days. Blood and saliva samples were collected on days 3, 4, 12, 13, 14, and 15. All samples were analyzed for total DMI content. Strong correlations were found between the blood samples collected 12, 24, and 32 h post dose (r=0.93, 0.96, 0.95) and saliva samples collected 24 and 32 h post single dose (r=0.91, 0.84) and the subjects' respective steady states. Although the correlation between blood and saliva levels was weaker (r=0.7) because of considerable interindividual variation in the saliva/plasma DMI ratio (16-fold variation), this ratio in individual subjects was stable. These data suggest that, as has been shown for other psychotropic drugs, single blood measures at 24 h post ingestion of 75 mg DMI can be used to predict optimal dosage in individual patients. Acceptable predictions of steady state plasma levels were obtained when this technique was applied to patient data available in the literature. It is also suggested that if the saliva/plasma ratio is established for each individual patient, their drug level monitoring may be possible using this noninvasive approach.

Key words

Desmethylimipramine Pharmacokinetics Saliva/plasma ratios Steady state prediction Single time point procedure 

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References

  1. Alexanderson B (1972a) Pharmacokinetics of nortriptyline in man after single and multiple doses: the predictability of steady-state plasma concentrations from single-dose plasma level data. Eur J Clin Pharmacol 4:82–91Google Scholar
  2. Alexanderson B (1972b) Pharmacokinetics of desmethylimipramine and nortriptyline in man after single and multiple oral doses — a cross-over study. Eur J Clin Pharmacol 5:1–10Google Scholar
  3. Braithwaite R, Montgomery S, Dawling S (1978) Nortriptyline in depressed patients with high plasma levels. Clin Pharmacol Ther 23:303–308Google Scholar
  4. Boxer GF, Jelinek V, Tompsett R, Du Bois R (1948) Streptomycin in the blood: chemical determinations after single and repeated intramuscular injections. J Pharmacol Exp Ther 92:226–235Google Scholar
  5. Brunswick DJ, Amsterdam JD, Mendels J, Stern SL (1979) Prediction of steady-state imipramine and desmethylimipramine plasma concentrations from single-dose data. Clin Pharmacol Ther 25:605–610Google Scholar
  6. Chang SS, Pandey GN, Casper R, Garver D, Davis JM (1977) Predicting the optimal lithium dosage. Proceedings of the American Society for Clinical Pharmacology and Therapeutics, Dallas, Tex., March 23–25Google Scholar
  7. Chang SS, Pandey GN, Casper RC, Kinard CO, Davis JM (1979) Pharmacokinetics of lithium: predicting optimal dosage. In: Cooper TB, Gershon S, Kline NS, Schou M (eds) Lithium controversies and unresolved issues. Excerpta Medica. Amsterdam, pp 419–426Google Scholar
  8. Cooper TB, Bergner P-EE, Simpson GM (1973) The 24-hour serum lithium level as a prognosticator of dosage requirements. Am J Psychiatry 130:601–603Google Scholar
  9. Cooper TB, Simpson GM (1976) The 24-hour lithium level as a prognosticator of dosage requirements: a 2-year follow-up study. Am J Psychiatry 133:440–443Google Scholar
  10. Cooper TB, Simpson GM (1978) Prediction of individual dosage of nortriptyline. Am J Psychiatry 135:333–335Google Scholar
  11. Cooper TB, Simpson GM (1975) A sensitive GLC method for the determination of imipramine and desmethylimipramine using a nitrogen detector. Psychopharmacol Commun 1:445–454Google Scholar
  12. Coppen A, Ghose K, Montgomery S, Rama Raa VA, Bailey J, Christiansen SJ, Mikkleson PL, van Praag HM, van de Poel F, Minsker EJ, Kozulja VJ, Matussek N, Kunkunz G, Jorgensen A (1978) Amitriptyline plasma-concentration and clinical effect. Lancet 1:63–66Google Scholar
  13. Danhof M, Breimer DD (1978) Therapeutic drug monitoring in saliva. Clin Pharmacokinet 3:39–57Google Scholar
  14. Doluisio JT, Dittert CW (1969) Influence of repetitive dosing of tetracyclines on biologic half-life in serum. Clin Pharmacol Ther 10:690–701Google Scholar
  15. Dost FH (1968) Grundlagen der Pharmakokinetik, 2. Aufl., S. 182–187. G Thieme, StuttgartGoogle Scholar
  16. Friedel RO, Veith RC, Bloom V, Bielski RJ (1979) Desipramine plasma levels and clinical response in depressed outpatients. Commun Psychopharmacol 3:81–88Google Scholar
  17. Galeazzi RL, Benet LZ, Sheiner LB (1976) Relationship between the pharmacokinetics and pharmacodynamics of procainamide. Clin Pharmacol Ther 20:278–289Google Scholar
  18. Gengo F, Timko J, D'Antonio J, Ramsey TA, Frazer A, Mendels J (1980) Prediction of dosage of lithium carbonate: Use of a standard predictive method. J Clin Psychiat 41:319–321Google Scholar
  19. Gram LF (1977) Plasma level monitoring of tricyclic antidepressant therapy. Clin Pharmacokinet 2:237–251Google Scholar
  20. Glassman AH, Perel JM, Shostak M, Kantor SJ, Fleiss JL (1977) Clinical implications of imipramine plasma levels for depressive illness. Arch Gen Psychiatry 34:197–204Google Scholar
  21. Jeffrey AA, Turner P (1978) Relationship between plasma and salivary concentrations of amitriptyline. Br J Clin Pharmacol 5:268–269Google Scholar
  22. Klein DF, Davis JM (1969) Diagnosis and drug treatment of psychiatric disorders. Baltimore, Williams and WilkinsGoogle Scholar
  23. Klerman GL (1972) Drug therapy of clinical depressions. J Psychiatr Res 9:253–270Google Scholar
  24. Kragh-Sorensen P (1978) Correlation between plasma levels of nortriptyline and clinical effects. Commun Psychopharmacol 2:451–456Google Scholar
  25. Kupfer DJ, Hanin I, Spiker DG, Grau C, Koble P (1977) Amitriptyline plasma levels and clinical response in primary depression. Clin Pharmacol Ther 22:902–911Google Scholar
  26. Matin SB, Wan SH, Karam J (1974) Pharmacokinetics of tolbutamide in man: prediction by tolbutamide concentration in saliva. Clin Pharmacol Ther 16:1052–1058Google Scholar
  27. May PRA, VanPutten T, Jenden DJ, Cho AK (1978) Test dose response in schizophrenia: chlorpromazine blood and saliva levels. Arch Gen Psychiatry 35:1091–1097Google Scholar
  28. Montgomery SA, McAuley R, Rani SJ, Montgomery DB, Braithwaite R, Dawling S (1979) Amitriptyline plasma concentration and clinical response. Br Med J 1:230–231Google Scholar
  29. Montgomery SA, McAuley R, Montgomery DB, Braithwaite RA, Dawling S (1979) Dosage adjustment from simple nortriptyline spot level predictor test in depressed patients. Clin Pharmacokinet 4:129–136Google Scholar
  30. Morris JB, Beck AT (1974) The efficacy of antidepressant drugs: a review of research (1958–1972). Arch Gen Psychiatry 30:667–674Google Scholar
  31. Mucklow JC, Bending MR, Kahn GC, Dollery CT (1978) Drug concentration in saliva. Clin Pharmacol Ther 24:563–570Google Scholar
  32. Muscettola G, Goodwin FK, Potter WZ, Claeys M, Markey SP (1978) Imipramine and desipramine in plasma and spinal fluid. Arch Gen Psychiatry 35:621–625Google Scholar
  33. Nagy A, Johansson R (1975) Plasma levels of imipramine and desimipramine in man after different routes of administration. Naunyn-Schmiedeberg's Arch Pharmacol 290:145–160Google Scholar
  34. Perel JM, Shostak M, Gann E, Kantor SJ, Glassman AH (1976) Pharmacodynamics of imipramine and clinical outcome in depressed patients. In: Gottschalk LA, Merlis S (eds) Pharmacokinetics of psychoactive drugs: blood levels and clinical response. Spectrum Publications, Inc., New YorkGoogle Scholar
  35. Potter WZ, Zavadil AP, Goodwin FK (1978) Prediction of steady-state plasma concentration of imipramine. Psychopharmacol Bull 14:29–32Google Scholar
  36. Rafaelsen O (1979) Report from the WHO Collaborative Reference Center for the study of psychotropic drugs in Denmark. The International References Center on Psychotropic Drugs — Activities, Plans, and New Briefs. Psychopharmacol Bull 2:2–3Google Scholar
  37. Rasmussen F (1964) Salivary excretion of sulphonamides and barbiturates in cows and goats. Acta Pharmacol Toxicol 21:11–19Google Scholar
  38. Reisby N, Gram LF, Bech P, Nagy A, Peterson GO, Ortmann J, Isben I, Dencker SJ, Jacobsen O, Krautwald O, Sondergaard I, Christiansen J (1977) Imipramine: clinical effects and pharmacokinetic variability. Psychopharmacology 54:263–272Google Scholar
  39. Risch SC, Huey LY, Janowsky DS (1979) Plasma levels of tricyclic antidepressants and clinical efficacy. I. Review of the literature. J Clin Psychiatry 40:4–16Google Scholar
  40. Ritschel WA (1974) Bioavailability testing and clinical significance. Pharm Acta Helv 49:77–83Google Scholar
  41. Ritschel WA, Erni W (1977) Pharmacokinetic comparison of the one-point method with other methods in predicting steady-state drug concentrations in multiple dosing. Int J Clin Pharmacol Biopharm 15:279–287Google Scholar
  42. Robinson DS, Cooper TB, Ravaris CL, Ives JO, Nies A, Bartlett D, Lamborn KR (1979) Plasma tricyclic drug levels in amitriptyline treated depressed patients. Psychopharmacology 63:223–231Google Scholar
  43. Seifert R, Bremkamp H, Junge C (1975) Veremfachte Lithiumeinstellung durch Belastungstest. Psychopharmacologia 43:285–286Google Scholar
  44. Sims A (1980) Monitoring lithium dose levels: estimation of lithium in saliva. In: Johnson FN (ed) Handbook of lithium therapy. MTP Press, EnglandGoogle Scholar
  45. Slattery JT, Gibaldi M, Koup JR (1980) Prediction of maintenance dose required to attain a desired drug concentration at steady-state from a single determination of concentration after an initial dose. Clin Pharmacokinet 5:377–385Google Scholar

Copyright information

© Springer-Verlag 1981

Authors and Affiliations

  • Thomas B. Cooper
    • 1
  • Nigel Bark
    • 1
  • George M. Simpson
    • 2
  1. 1.Rockland Research InstituteOrangeburgUSA
  2. 2.Adult Psychiatric Clinic1937 Hospital PlaceLos AngelesUSA

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