TABLE 2. The relative potency (expressed as the Ki [mol/L]) of selective serotonin reuptake inhibitors/active metabolites in inhibiting the functional integrity of cytochrome P450 (CYP) enzymes (CYP1A2, CYP2D6 and CYP3A3/4), based on in-vitro studies using human hepatic microsomes (from Preskorn, with permission.)

Citalopram/ Fluvoxamine/ Sertraline/
Reference Substrate demethylcitalopram Fluvoxamine norfluoxetine Paroxetine/M2 demethylsertraline
CYP1A1/2
Brosen et al. (Brosen K, Skjelbo E, Rasmussen BB, Poulsen HE, Loft S. Fluvoxamine is a potent inhibitor of cytochrome P4501A2. Biochem Pharmacol 1993;45:1211-1214. ) Phenacetin >100/>100

0.2

 >100/>100 45/NA 70/NA
Rasmussen et al. (Rasmussen B, Maenpaa J, Loft S, Poulsen H, Lykkesfeldt J, Brosen K. Selective serotonin reuptake inhibitors and theophylline metabolism in human liver microsomes: potent inhibition by fluvoxamine. Br J Clin Pharmacol 1995;39:151-159. ) Theophline >100/>100

0.2

 >100/>100

50

 >100
von Moltke et al. (von Moltke LL, Greenblatt DJ, Duan SX, Schmider J, Harmatz JS, Shader RI. In vitro biotransformation of phenacetin to acetaminophen: metabolic inhibition by antidepressants. Am Soc Clin Pharmacol Ther 1996;59:175. )

CYP2C19

 Phenacetin NA

0.24

 4.4/5.9

5.5

 8.8/9.5
Kobayashi (Kobayashi K, Yamumoto T, Chiba K, Tani M, Ishizaki T, Kuroiwa Y. The effects of selective serotonin reuptake inhibitors and their metabolites on S-mephenytoin 4'-hydroxylase activity in human liver microsomes. Br J Clin Pharmacol 1995;40:481-485. ) S-mephenytoin 87.3/55.8 NA 5.2/1.1

7.7

 2.0/N.A.
CYP2D6
Crewe et al. (Crewe HK, Lennard MS, Tucker GT, Woods FR, Haddock RE. The effect of paroxetine and other specific serotonin re-uptake inhibitors on cytochrome P450IID6 activity in human liver microsomes. Br J Clin Pharmacol 1991;32:658P-659P. ) Sparteine

5.1

8.2

 0.60/0.45 0.15/0.050 0.70/NA
Skelbo et al. (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. ) Imipramine NA

16.6

 3.0/3.5 2.0/NA 22.7/16.0
Otton et al. (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. ) Dextromethorphan NA NA 0.15/NA 0.065/NA 1.2/NA
Otton et al. (Otton SV, Ball SE, Cheung SW, Inaba T, Sellers EM. Comparative inhibition of the polymorphic enzyme CYP2D6 by venlafaxine (VF) and other 5HT uptake inhibitors. Clin Pharmacol Ther 1994;55:141. ) Dextromethorphan NA NA 0.17/0.19 NA 1.5/NA
CYP3A3/4a
von Moltke et al. (von Moltke LL, Greenblatt DJ, Duan SX, Harmatz JS, Shader RI. In vitro prediction of the terfenadine-ketoconazole pharmacokinetic interaction. J Clin Pharmacol 1994;34:1222-1227. ) Alprazolam NA

10

 83.3/11/1 39/NA 23.8/20.4
Rasmussen et al. (Rasmussen B, Maenpaa J, Loft S, Poulsen H, Lykkesfeldt J, Brosen K. Selective serotonin reuptake inhibitors and theophylline metabolism in human liver microsomes: potent inhibition by fluvoxamine. Br J Clin Pharmacol 1995;39:151-159. ) Cortisol >100/>100

40

 60/19 >70

90

a Ki value for comparison: ketoconaxole =0.05 (96)

Abbreviations: Ki = inhibition constant (the smaller the value, the greater the potency on a molar basis); NA = data not available.

Back to Chapter

published 2000