CYP2D6 inhibition by selective serotonin reuptake inhibitors: analysis of achievable steady-state plasma concentrations and the effect of ultrarapid metabolism at CYP2D6.
OBJECTIVE
To assess the correlation between plasma concentrations of four commonly administered selective serotonin reuptake inhibitors (SSRIs) and the magnitude of cytochrome P450 (CYP) 2D6 inhibition.


METHODS
Prospective analysis.


METHODS
University-affiliated research laboratory.


METHODS
Thirty-two healthy, drug-free volunteers.


METHODS
Subjects were randomized to four groups and received daily administration of either fluoxetine 60 mg (as a loading dose), fluvoxamine 100 mg, paroxetine 20 mg, or sertraline 100 mg for 8 days.


RESULTS
The urinary concentration ratio of dextromethorphan:dextrorphan (interpreted as an in vivo index of CYP2D6 activity) was determined for each subject before and after the 8 days of receiving SSRIs. Plasma SSRI trough concentrations were measured on days 6-9. The CYP2D6 genotype was determined in a subject with an undetectable paroxetine concentration. Inhibition of CYP2D6 correlated significantly with plasma concentrations of paroxetine and fluoxetine. In contrast, no significant correlations emerged between CYP2D6 inhibition and plasma concentrations of sertraline or fluvoxamine. The subject with an undetectable paroxetine concentration was found to carry at least three functional CYP2D6 genes.


CONCLUSIONS
For paroxetine and fluoxetine, plasma concentrations and dosage strongly influence the magnitude of enzyme inhibition. The potential of paroxetine (a CYP2D6 substrate) as an inhibitor may be affected by the genotypes and metabolic capacities of individual subjects.
Lam
Y W Francis
YW
Department of Pharmacology, University of Texas Health Science Center at San Antonio, 78284-6220, USA. lamf@uthscsa.edu
Gaedigk
Andrea
A
Ereshefsky
Larry
L
Alfaro
Cara L
CL
Simpson
Joe
J
D016861:Cyclooxygenase Inhibitors / Q000097:blood* / Q000494:pharmacology*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003915:Dextromethorphan / Q000378:metabolism; D003917:Dextrorphan / Q000378:metabolism; D005473:Fluoxetine / Q000097:blood / Q000494:pharmacology; D016666:Fluvoxamine / Q000097:blood / Q000494:pharmacology; D005838:Genotype; D006801:Humans; D017374:Paroxetine / Q000097:blood / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000097:blood* / Q000494:pharmacology*; D020280:Sertraline / Q000097:blood / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D019389:Cytochrome P-450 CYP2D6; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003915:Dextromethorphan; D003917:Dextrorphan; D005473:Fluoxetine; D016666:Fluvoxamine; D017374:Paroxetine; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline