Purpose: This study evaluated the effects of cytochrome P450 (CYP) 2D6 polymorphisms on the pharmacokinetics of controlled-release paroxetine in healthy Chinese subjects and used paroxetine as a tool drug to compare the performance of traditional phenotype and activity score systems.
Methods: Pharmacokinetic data were evaluated in 24 subjects who received a single oral dose of 25 mg controlled-release paroxetine. Plasma paroxetine concentrations were measured by LC-MS/MS. CYP2D6 genotypes were tested by PCR and direct DNA sequencing. Subjects were classified by two systems of phenotype prediction. In the traditional phenotype system, subjects were classified as extensive metabolizers or intermediate metabolizers; in the activity score system, subjects were divided into four activity groups. Analysis of variance testing was applied to estimate the effects of CYP2D6 polymorphisms on the pharmacokinetics of paroxetine.
Results: With the traditional phenotype system, significant differences were observed in the following pharmacokinetic parameters of paroxetine: t 1/2, C max, AUC0-t, AUC0-inf, Vz/F, and CL/F (all P < 0.05). The AUC or exposure of paroxetine was about 3.5-fold higher in the intermediate metabolizer group than in the extensive metabolizer group. With the activity score system, significant differences were observed in the t 1/2, C max, AUC0-t, AUC0-inf, Vz/F, and CL/F among the four different activity score groups (all P < 0.05). We found that the AUC of paroxetine decreased by around one half as the activity score increased by 0.5.
Conclusion: The pharmacokinetics of controlled-release paroxetine after a single administration was affected by CYP2D6 polymorphisms. Both the traditional phenotype and the activity score systems performed well and distinguished subjects with different drug exposures. The activity score system provided a more detailed classification for the subjects.