Analysis of Achievable Steady-State Plasma Concentrations
Analysis of Achievable Steady-State Plasma Concentrations
Study 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.
Design: Prospective analysis.
Setting: University-affiliated research laboratory.
Patients: Thirty-two healthy, drug-free volunteers.
Intervention: 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.
Measurements and Main 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.
Most reports of metabolic enzyme inhibition by selective serotonin reuptake inhibitors (SSRIs) have focused on changes in concentration of the affected drug. For example, studies have addressed elevated desipramine concentrations with paroxetine, increases in imipramine concentrations with fluvoxamine, and increased phenytoin concentrations with sertraline. In contrast, the concentration of the inhibitor rarely has been measured or discussed. Due to interindividual variability in drug disposition, plasma concentrations of SSRIs vary significantly among individuals. Despite the potential role of variable inhibitor concentration as a determinant of interindividual differences in enzyme inhibition, this relationship has not been addressed adequately with clinical data.
In a previous study, we found that the extent of cytochrome P450 (CYP) 2D6 inhibition varied significantly among 31 healthy subjects who had received fluvoxamine, fluoxetine, sertraline, or paroxetine. In this study, we further examined the same group of subjects with attention to the role of achievable steady-state trough plasma concentrations of these four SSRIs and applicable metabolites, as well as subject-related variables, on CYP2D6 inhibition. The ratio of urinary dextromethorphan (DM):dextrorphan (DX) was used as an in vivo, noninvasive index of CYP2D6 activity. Trough SSRI concentrations were assessed because the appropriate sampling time is much better defined than that for peak concentrations. Moreover, trough concentration is measured more frequently in clinical practice.
Study 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.
Design: Prospective analysis.
Setting: University-affiliated research laboratory.
Patients: Thirty-two healthy, drug-free volunteers.
Intervention: 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.
Measurements and Main 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.
Most reports of metabolic enzyme inhibition by selective serotonin reuptake inhibitors (SSRIs) have focused on changes in concentration of the affected drug. For example, studies have addressed elevated desipramine concentrations with paroxetine, increases in imipramine concentrations with fluvoxamine, and increased phenytoin concentrations with sertraline. In contrast, the concentration of the inhibitor rarely has been measured or discussed. Due to interindividual variability in drug disposition, plasma concentrations of SSRIs vary significantly among individuals. Despite the potential role of variable inhibitor concentration as a determinant of interindividual differences in enzyme inhibition, this relationship has not been addressed adequately with clinical data.
In a previous study, we found that the extent of cytochrome P450 (CYP) 2D6 inhibition varied significantly among 31 healthy subjects who had received fluvoxamine, fluoxetine, sertraline, or paroxetine. In this study, we further examined the same group of subjects with attention to the role of achievable steady-state trough plasma concentrations of these four SSRIs and applicable metabolites, as well as subject-related variables, on CYP2D6 inhibition. The ratio of urinary dextromethorphan (DM):dextrorphan (DX) was used as an in vivo, noninvasive index of CYP2D6 activity. Trough SSRI concentrations were assessed because the appropriate sampling time is much better defined than that for peak concentrations. Moreover, trough concentration is measured more frequently in clinical practice.
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