Clinical Pharmacokinetics

, Volume 46, Issue 4, pp 281–290

The Clinical Pharmacokinetics of Escitalopram

Review Article
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Abstract

Escitalopram is the (S)-enantiomer of the racemic selective serotonin reuptake inhibitor antidepressant citalopram. Clinical studies have shown that escitalopram is effective and well tolerated in the treatment of depression and anxiety disorders. Following oral administration, escitalopram is rapidly absorbed and reaches maximum plasma concentrations in approximately 3–4 hours after either single-or multiple-dose administration. The absorption of escitalopram is not affected by food. The elimination half-life of escitalopram is about 27–33 hours and is consistent with once-daily administration. Steady-state concentrations are achieved within 7–10 days of administration. Escitalopram has low protein binding (56%) and is not likely to cause interactions with highly protein-bound drugs. It is widely distributed throughout tissues, with an apparent volume of distribution during the terminal phase after oral administration (Vz/F) of about 1100L. Unmetabolised escitalopram is the major compound in plasma. S-demethylcitalopram (S-DCT), the principal metabolite, is present at approximately one-third the level of escitalopram; however, S-DCT is a weak inhibitor of serotonin reuptake and does not contribute appreciably to the therapeutic activity of escitalopram. The didemethyl metabolite of escitalopram (S-DDCT) is typically present at or below quantifiable concentrations. Escitalopram and S-DCT exhibit linear and dose-proportional pharmacokinetics following single or multiple doses in the 10–30 mg/day dose range. Adolescents, elderly individuals and patients with hepatic impairment do not have clinically relevant differences in pharmacokinetics compared with healthy young adults, implying that adjustment of the dosage is not necessary in these patient groups. Escitalopram is metabolised by the cytochrome P450 (CYP) isoenzymes CYP2C19, CYP2D6 and CYP3A4. However, ritonavir, a potent inhibitor of CYP3A4, does not affect the pharmacokinetics of escitalopram. Coadministration of escitalopram 20mg following steady-state administration of cimetidine or omeprazole led to a 72% and 51% increase, respectively, in escitalopram exposure compared with administration alone. These changes were not considered clinically relevant. In vitro studies have shown that escitalopram has negligible inhibitory effects on CYP isoenzymes and P-glycoprotein, suggesting that escitalopram is unlikely to cause clinically significant drug-drug interactions. The favourable pharmacokinetic profile of escitalopram suggests clinical utility in a broad range of patients.

References

  1. 1.
    Burke WJ. Escitalopram. Expert Opin Investig Drugs 2002; 11(10): 1477–86PubMedCrossRefGoogle Scholar
  2. 2.
    Hyttel J, Bogeso KP, Perregaard J, et al. The pharmacological effect of citalopram resides in the (S)-(+)-enantiomer. J Neural Transm Gen Sect 1992; 88(2): 157–60PubMedCrossRefGoogle Scholar
  3. 3.
    Sanchez C, Bergqvist PB, Brennum LT, et al. Escitalopram, the S-(+)-enantiomer of citalopram, is a selective serotonin reuptake inhibitor with potent effects in animal models predictive of antidepressant and anxiolytic activities. Psychopharmacology (Berl) 2003; 167(4): 353–62Google Scholar
  4. 4.
    Sanchez C, Bogeso KP, Ebert B, et al. Escitalopram versus citalopram: the surprising role of the R-enantiomer. Psychopharmacology (Berl) 2004; 174(2): 163–76CrossRefGoogle Scholar
  5. 5.
    Owens MJ, Knight DL, Nemeroff CB. Second-generation SS-RIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine. Biol Psychiatry 2001; 50(5): 345–50PubMedCrossRefGoogle Scholar
  6. 6.
    von Moltke LL, Greenblatt DJ, Giancarlo GM, et al. Escitalopram (S-citalopram) and its metabolites in vitro: cytochromes mediating biotransformation, inhibitory effects, and comparison to R-citalopram. Drug Metab Dispos 2001; 29(8): 1102–9Google Scholar
  7. 7.
    Stahl SM, Gergel I, Li D. Escitalopram in the treatment of panic disorder: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2003; 64(11): 1322–7PubMedCrossRefGoogle Scholar
  8. 8.
    Burke WJ, Gergel I, Bose A. Fixed-dose trial of the single isomer SSRI escitalopram in depressed outpatients. J Clin Psychiatry 2002; 63(4): 331–6PubMedCrossRefGoogle Scholar
  9. 9.
    Wade A, Michael Lemming O, Bang Hedegaard K. Escitalopram 10 mg/day is effective and well tolerated in a placebo-controlled study in depression in primary care. Int Clin Psychopharmacol 2002; 17(3): 95–102PubMedCrossRefGoogle Scholar
  10. 10.
    Rapaport MH, Bose A, Zheng H. Escitalopram continuation treatment prevents relapse of depressive episodes. J Clin Psychiatry 2004; 65(1): 44–9PubMedCrossRefGoogle Scholar
  11. 11.
    Waugh J, Goa KL. Escitalopram: a review of its use in the management of major depressive and anxiety disorders. CNS Drugs 2003; 17(5): 343–62PubMedCrossRefGoogle Scholar
  12. 12.
    Davidson JR, Bose A, Korotzer A, et al. Escitalopram in the treatment of generalized anxiety disorder: double-blind, placebo controlled, flexible-dose study. Depress Anxiety 2004; 19(4): 234–40PubMedCrossRefGoogle Scholar
  13. 13.
    Montgomery SA, Loft H, Sanchez C, et al. Escitalopram (S-enantiomer of citalopram): clinical efficacy and onset of action predicted from a rat model. Pharmacol Toxicol 2001; 88(5): 282–6PubMedCrossRefGoogle Scholar
  14. 14.
    Gorman JM, Korotzer A, Su G. Efficacy comparison of escitalopram and citalopram in the treatment of major depressive disorder: pooled analysis of placebo-controlled trials. CNS Spectrums 2002; 7 (4 Suppl.1): 40–4Google Scholar
  15. 15.
    Drewes P, Thijssen I, Mengel H, et al. A single-dose cross-over pharmacokinetic study comparing racemic citalopram (40 mg) with the S-enantiomer of citalopram (escitalopram, 20 mg) in healthy male subjects [abstract]. National Institute of Mental Health/41 st Annual New Clinical Drug Evaluation Unit Meeting, 2001 May 28–31; Phoenix (AZ) [online]. Available from URL: http://www.nimh.nih.gov/ncdeu/abstracts2001/ncdeu2045.cfm [Accessed 2006 Nov 8]
  16. 16.
    Sogaard B, Mengel H, Rao N, et al. The pharmacokinetics of escitalopram after oral and intravenous administration of single and multiple doses to healthy subjects. J Clin Pharmacol 2005; 45(12): 1400–6PubMedCrossRefGoogle Scholar
  17. 17.
    Joffe P, Larsen FS, Pedersen V, et al. Single-dose pharmacokinetics of citalopram in patients with moderate renal insufficiency or hepatic cirrhosis compared with healthy subjects. Eur J Clin Pharmacol 1998; 54(3): 237–42PubMedCrossRefGoogle Scholar
  18. 18.
    Sidhu J, Priskorn M, Poulsen M, et al. Steady-state pharmacokinetics of the enantiomers of citalopram and its metabolites in humans. Chirality 1997; 9(7): 686–92PubMedCrossRefGoogle Scholar
  19. 19.
    Rochat B, Amey M, Baumann P. Analysis of enantiomers of citalopram and its demethylated metabolites in plasma of depressive patients using chiral reverse-phase liquid chromatography. Ther Drug Monit 1995; 17(3): 273–9PubMedCrossRefGoogle Scholar
  20. 20.
    Forest Pharmaceuticals, Inc. Prescribing information for Lexapro (escitalopram oxalate). St Louis (MO): Forest Pharmaceuticals, Inc., 2006 [online]. Available from URL: http://www.lexapro.com/pdf/lexapro_pi.pdf [Accessed 2007 Feb 22]
  21. 21.
    Gutierrez M, Mengel H. Pharmacokinetics of escitalopram [abstract]. National Institute of Mental Health/42nd Annual New Clinical Drug Evaluation Unit Meeting, June 10–13, 2002; Boca Raton, FL [online]. Available from URL: http://www.nimh.nih.gov/ncdeu/abstracts2002/ncdeu2002.cfm [Accessed 2006 Nov 8]
  22. 22.
    Uhr M, Grauer MT. abcblab P-glycoprotein is involved in the uptake of citalopram and trimipramine into the brain of mice. J Psychiatr Res 2003; 37(3): 179–85PubMedCrossRefGoogle Scholar
  23. 23.
    Uhr M, Grauer MT, Holsboer F. Differential enhancement of antidepressant penetration into the brain in mice with abcblab (mdrlab) P-glycoprotein gene disruption. Biol Psychiatry 2003; 54(8): 840–6PubMedCrossRefGoogle Scholar
  24. 24.
    Uhr M, Steckler T, Yassouridis A, et al. Penetration of amitriptyline, but not of fluoxetine, into brain is enhanced in mice with blood-brain barrier deficiency due to mdrla P-glycoprotein gene disruption. Neuropsychopharmacology 2000; 22(4): 380–7PubMedCrossRefGoogle Scholar
  25. 25.
    Rochat B, Baumann P, Audus KL. Transport mechanisms for the antidepressant citalopram in brain microvessel endothelium. Brain Res 1999; 831(1–2): 229–36PubMedCrossRefGoogle Scholar
  26. 26.
    Oyehaug E, Ostensen ET, Salvesen B. High-performance liquid chromatographic determination of citalopram and four of its metabolites in plasma and urine samples from psychiatric patients. J Chromatogr 1984; 308: 199–208PubMedCrossRefGoogle Scholar
  27. 27.
    Rochat B, Amey M, Van Gelderen H, et al. Determination of the enantiomers of citalopram, its demethylated and propionic acid metabolites in human plasma by chiral HPLC. Chirality 1995; 7(6): 389–95PubMedCrossRefGoogle Scholar
  28. 28.
    Desta Z, Zhao X, Shin JG, et al. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 2002; 41(12): 913–58PubMedCrossRefGoogle Scholar
  29. 29.
    Herrlin K, Yasui-Furukori N, Tybring G, et al. Metabolism of citalopram enantiomers in CYP2C19/CYP2D6 phenotyped panels of healthy Swedes. Br J Clin Pharmacol 2003; 56(4): 415–21PubMedCrossRefGoogle Scholar
  30. 30.
    Rochat B, Kosel M, Boss G, et al. Stereoselective biotransformation of the selective serotonin reuptake inhibitor citalopram and its demethylated metabolites by monoamine oxidases in human liver. Biochem Pharmacol 1998; 56(1): 15–23PubMedCrossRefGoogle Scholar
  31. 31.
    Kosel M, Gnerre C, Voirol P, et al. In vitro biotransformation of the selective serotonin reuptake inhibitor citalopram, its enantiomers and demethylated metabolites by monoamine oxidase in rat and human brain preparations. Mol Psychiatry 2002; 7(2): 181–8PubMedCrossRefGoogle Scholar
  32. 32.
    Kragh-Sorensen P, Overo KF, Petersen OL, et al. The kinetics of citalopram: single and multiple dose studies in man. Acta Pharmacol Toxicol (Copenh) 1981; 48(1): 53–60CrossRefGoogle Scholar
  33. 33.
    Dalgaard L, Larsen C. Metabolism and excretion of citalopram in man: identification of O-acyl- and N-glucuronides. Xenobiotica 1999; 29(10): 1033–41PubMedCrossRefGoogle Scholar
  34. 34.
    Periclou A, Rao N, Sherman T, et al. Single-dose pharmacokinetic study of escitalopram in adolescents and adults [abstract]. Pharmacotherapy 2003; 23(10): 1361–2Google Scholar
  35. 35.
    Areberg J, Christophersen JS, Poulsen MN, et al. The pharmacokinetics of escitalopram in patients with hepatic impairment. AAPS J 2006; 8(1): E14–9PubMedCrossRefGoogle Scholar
  36. 36.
    Greenblatt DJ, von Moltke LL, Harmatz JS, et al. Drug interactions with newer antidepressants: role of human cytochromes P450. J Clin Psychiatry 1998; 59 Suppl. 15: 19–27PubMedGoogle Scholar
  37. 37.
    Ketter TA, Flockhart DA, Post RM, et al. The emerging role of cytochrome P450 3A in psychopharmacology. J Clin Psychopharmacol 1995; 15(6): 387–98PubMedCrossRefGoogle Scholar
  38. 38.
    Harvey AT, Preskorn SH. Cytochrome P450 enzymes: interpretation of their interactions with selective serotonin reuptake inhibitors. Part II. J Clin Psychopharmacol 1996; 16(5): 345–55PubMedCrossRefGoogle Scholar
  39. 39.
    Hemeryck A, De Vriendt C, Belpaire FM. Inhibition of CYP2C9 by selective serotonin reuptake inhibitors: in vitro studies with tolbutamide and (S)-warfarin using human liver microsomes. Eur J Clin Pharmacol 1999; 54(12): 947–51PubMedCrossRefGoogle Scholar
  40. 40.
    Lane RM. Pharmacokinetic drug interaction potential of selective serotonin reuptake inhibitors. Int Clin Psychopharmacol 1996; 11 Suppl. 5: 31–61PubMedCrossRefGoogle Scholar
  41. 41.
    Hemeryck A, Belpaire FM. Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug interactions: an update. Curr Drug Metab 2002; 3(1): 13–37PubMedCrossRefGoogle Scholar
  42. 42.
    Brosen K, Skjelbo E, Rasmussen BB, et al. Fluvoxamine is a potent inhibitor of cytochrome P4501A2. Biochem Pharmacol 1993; 45(6): 1211–4PubMedCrossRefGoogle Scholar
  43. 43.
    Rasmussen BB, Nielsen TL, Brosen K. Fluvoxamine inhibits the CYP2C19-catalysed metabolism of proguanil in vitro. Eur J Clin Pharmacol 1998; 54(9–10): 735–40PubMedCrossRefGoogle Scholar
  44. 44.
    Gutierrez MM, Rosenberg J, Abramowitz W. An evaluation of the potential for pharmacokinetic interaction between escitalopram and the cytochrome P450 3A4 inhibitor ritonavir. Clin Ther 2003; 25(4): 1200–10PubMedCrossRefGoogle Scholar
  45. 45.
    Mailing D, Poulsen MN, Sogaard B. The effect of cimetidine or omeprazole on the pharmacokinetics of escitalopram in healthy subjects. Br J Clin Pharmacol 2005; 60(3): 287–90CrossRefGoogle Scholar
  46. 46.
    Gram LF, Hansen MG, Sindrup SH, et al. Citalopram: interaction studies with levomepromazine, imipramine, and lithium. Ther Drug Monit 1993; 15(1): 18–24PubMedCrossRefGoogle Scholar
  47. 47.
    Baettig D, Bondolfi G, Montaldi S, et al. Tricyclic antidepressant plasma levels after augmentation with citalopram: a case study. Eur J Clin Pharmacol 1993; 44(4): 403–5PubMedCrossRefGoogle Scholar
  48. 48.
    Larsen F, Priskorn M, Overo KF. Lack of citalopram effect on oral digoxin pharmacokinetics. J Clin Pharmacol 2001; 41(3): 340–6PubMedCrossRefGoogle Scholar
  49. 49.
    Baumann P, Nil R, Souche A, et al. A double-blind, placebo-controlled study of citalopram with and without lithium in the treatment of therapy-resistant depressive patients: a clinical, pharmacokinetic, and pharmacogenetic investigation. J Clin Psychopharmacol 1996; 16(4): 307–14PubMedCrossRefGoogle Scholar
  50. 50.
    Nolting A, Abramowitz W. Lack of interaction between citalopram and the CYP3A4 substrate triazolam. Pharmacotherapy 2000; 20(7): 750–5PubMedCrossRefGoogle Scholar
  51. 51.
    Priskorn M, Sidhu JS, Larsen F, et al. Investigation of multiple dose citalopram on the pharmacokinetics and pharmacodynamics of racemic warfarin. Br J Clin Pharmacol 1997; 44(2): 199–202PubMedCrossRefGoogle Scholar
  52. 52.
    Möller SE, Larsen F, Pitsiu M, et al. Effect of citalopram on plasma levels of oral theophylline. Clin Ther 2000; 22(12): 1494–501PubMedCrossRefGoogle Scholar
  53. 53.
    Steinacher L, Vandel P, Zullino DF, et al. Carbamazepine augmentation in depressive patients non-responding to citalopram: a pharmacokinetic and clinical pilot study. Eur Neuropsychopharmacol 2002; 12(3): 255–60PubMedCrossRefGoogle Scholar
  54. 54.
    Möller SE, Larsen F, Khant AZ, et al. Lack of effect of citalopram on the steady-state pharmacokinetics of carbamazepine in healthy male subjects. J Clin Psychopharmacol 2001; 21(5): 493–9PubMedCrossRefGoogle Scholar
  55. 55.
    Bondolfi G, Chautems C, Rochat B, et al. Non-response to citalopram in depressive patients: pharmacokinetic and clinical consequences of a fluvoxamine augmentation. Psychopharmacology (Berl) 1996; 128(4): 421–5CrossRefGoogle Scholar
  56. 56.
    Bondolfi G, Lissner C, Kosel M, et al. Fluoxetine augmentation in citalopram non-responders: pharmacokinetic and clinical consequences. Int J Neuropsychopharmacol 2000; 3(1): 55–60PubMedCrossRefGoogle Scholar
  57. 57.
    Weiss J, Dormann SM, Martin-Facklam M, et al. Inhibition of P-glycoprotein by newer antidepressants. J Pharmacol Exp Ther 2003; 305(1): 197–204PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2007

Authors and Affiliations

  1. 1.Kyowa Pharmaceutical, Inc.PrincetonUSA

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