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The relationship between paroxetine and the sparteine oxidation polymorphism
S H Sindrup1, K Brøsen, L F Gram
1Department of Clinical Pharmacology, Odense University, Denmark.
Clinical Pharmacology and Therapeutics
|March 1, 1992
Summary
Paroxetine, a selective serotonin reuptake inhibitor, potently inhibits sparteine oxidation by CYP2D6. This drug interaction is more pronounced after single doses than at steady-state due to enzyme saturation in extensive metabolizers.
Area of Science:
- Pharmacology
- Drug Metabolism
- Pharmacogenetics
Background:
- Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed.
- Individual variability in drug response is often linked to genetic polymorphisms in drug-metabolizing enzymes.
- Sparteine oxidation is a well-established probe for CYP2D6 activity.
Purpose of the Study:
- To investigate the in vivo interaction between paroxetine and sparteine metabolism.
- To determine the effect of paroxetine on CYP2D6 activity in individuals with different sparteine oxidation phenotypes.
Main Methods:
- A combined single-dose and steady-state study design.
- Inclusion of extensive and poor metabolizers of sparteine.
- Pharmacokinetic analysis of paroxetine and sparteine metabolic ratio (MR) determination.
Main Results:
- Paroxetine AUC was significantly higher in poor metabolizers than extensive metabolizers, with a less pronounced difference at steady-state.
- Paroxetine significantly inhibited sparteine metabolism in extensive metabolizers, altering their phenotype.
- Inhibition of sparteine metabolism was reversible upon paroxetine cessation.
Conclusions:
- Paroxetine is a potent inhibitor of CYP2D6 in vivo.
- Paroxetine and sparteine metabolism cosegregate, indicating shared metabolic pathways.
- The interphenotype difference in paroxetine metabolism is less prominent at steady-state due to CYP2D6 saturation in extensive metabolizers.
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