TABLE 4. Summary of formal in vivo studies of the effects of different serotonin selective reuptake inhibitors (SSRIs) on CYP 2D6 model substrates



SSRI

Author

No		 SSRI treatment:
Dose (mg/day) x
Duration (days)

Substrate
Substrate
dosing

Results
            AUC2-AUC1 AUC1 DM/DO Ems to PMs
Citalopram Gram (Gram LF, Hansen MGJ, Sindrup SH, et al. Citalopram: interaction studies with levomepromazine, imipramine, and lithium. Ther Drug Monit 1993;15:18-24. ) 8
    40 mg/d x 10 days
DMI Single dose ­ 47%    
Fluoxetine Lam 8
    60* mg/d x 8 days
 DM Single dose   ­ 3484%
    62.5%
  Amchin 12
    20mg/d x 28 days
 DM Single dose   ­ 1711%
     
  Bergstrom (Bergstrom RF, Peyton AL, Lemberger L. Quantification and mechanism of the fluoxetine and tricyclic antidepressant interaction. Clin Pharmacol Ther 1992;51:239-248. ) 6
    60*mg/d x 8 days
 DMI Single dose ­ 640%  
     
    6
    60*mg/d x 8 days
 IMI Single dose IMI ­ 235%
DMI ­ 430%
Total ­ 327%		  
     
  Preskorn () 9
    20mg/d x 21 days
 DMI 21 days ­ 380%  
     
  Otton (Otton SV, Wu D, Joffe RT, Cheung SW, Sellers EM. Inhibition by fluoxetine of cytochrome P450 2D6 activity. Clin Pharmacol Ther 1993;53:401-409. ) 19
    37 ± 17mg/d x 21d
 DM Single dose    
    95%
  Maes 11
    20mg/d x 28 days
 mCPP 7 days ­ 820%( 270%) #  
     
Fluvoxamine Lam 8
    100mg/d x 8 days
 DM Single dose   ­ 6%
    0%
  Spina (Spina E, Pollicino AM, Avenoso A, Campo GM, Perucca E, Caputi AP. Effect of fluvoxamine on the pharmacokinetics of imipramine and desipramine in healthy subjects. Ther Drug Monit 1993;15:243-246. ) 16
    100mg/d x 10days
 IMI Single dose ­ 263%  
     
    6
    100mg/d x 10 days
 DMI Single dose ­ 14%  
     
Paroxetine Alderman (Preskorn S, Alderman J, Greenblatt D, Horst W. Sertraline does not inhibit cytochrome (CYP) 3A-mediated drug metabolism in vivo. Psychopharmacol Bull 1997;33:659-665. ) 17
    20mg/d x 9 days
 DMI 9 days ­ 421%  
     
  Brosen (Brosen K, Hansen JG, Neilsen KK, Sindrup SH, Gram LF. Inhibition by paroxetine of desipramine metabolism in extensive but not in poor metabolizers of sparteine. Eur J Clin Pharmacol 1993;44:349-355. ) 9
    20mg/d x 8 days
 DMI Single dose ­ 364%  
    78%
  Albers (Albers LJ, Reist C, Helmeste D, Vu R, Tang SW. Paroxetine shifts imipramine metabolism. Psychiatr Res 1996;59:189-196. ) 10
    30mg/d x 4 days
 IMI Single dose ­ IMI 74%
­ DMI 327%
­ Total 223% 		 
     
  Lam 8
    20mg/d x 8 days
 DM Single dose   ­ 3943%
    50%
  Ozdemir 8
    20mg/d x 10 days
 PRZ Single dose ­ 595%  
     
Sertraline Preskorn () 9
    50mg/d x 21 days
 DMI 21 days ­ 23%  
     
  Jann (Jann M, Carson S, Grimsley S, Erikson S, Kumar A, Carter J. Effects of sertraline (SER) upon imipramine (IMI) pharmacodynamics. Clin Pharmacol Ther 1995;57:207 ) 4
    50mg/d x 7 days
 DMI 7 days ­ 0%  
     
  Alderman (Preskorn S, Alderman J, Greenblatt D, Horst W. Sertraline does not inhibit cytochrome (CYP) 3A-mediated drug metabolism in vivo. Psychopharmacol Bull 1997;33:659-665. ) 17
    50mg/d x 9 days
 DMI 9 days ­ 37%  
     
  Ozdemir 19
    94 ± 26mg/d x 24 ± 17 days
 DM Single dose ­ 0%  
     
  Sproule 6
    108 ± 49mg/d x 21d
 DM Single dose ­ 5% ­ 22%
    0%
  Lam 7
    100mg/d x 8 days
 DM Single dose   ­ 28%
    0%
  Kurtz 6
    150mg/d x 8 days
 IMI Single dose ­ 68%  
     
    6
    150mg/d x 8 days
 DMI Single dose ­ 54%  
     
  Zussman (105.	Zussman B, Davie C, Fowles S, et al. Sertraline, ) 13
    150mg/d x 29 days
 DMI Single dose ­ 70%  
     
  Solai 7
    114 ± 24mg/d x ?d
 NTP Chronic dosing ­ 70%  
     

AUC1 = Area Under the Curve of the substrate without SSRI, AUC2 = Area Under the Curve with SSRI

DMI = desipramine, IMI = imipramine, DM = dextromethrophan, DO = dextrophan,

mCPP = meta-chlorophenypiperazine (a metabolite of trazadone), PRZ = perphenazine,

NTP = nortriptyline

* 60 mg/day for 8 days is used to simulate a dose of 20mg dy under steady state

# 820% is based on all the data. If the highest two increases are excluded the average was 270%

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published 2000