The CYP2D6 polymorphism in relation to the metabolism of amitriptyline and nortriptyline in the Faroese population

Abstract

Aim: To determine the frequency of CYP2D6 poor metabolizers (PMs) in a Faroese patient group medicated with amitriptyline (AT) and to investigate plasma concentrations of AT and metabolites in relation to CYP2D6.

Methods: CYP2D6 phenotype and genotype were determined in 23 Faroese patients treated with AT. Plasma concentrations of AT and metabolites were determined by high-performance liquid chromatography and investigated in relation to CYP2D6 activity.

Results: Of the 23 patients phenotyped and genotyped, five (22%) (95% confidence interval 7.5, 43.7) were CYP2D6 PMs. No difference was found in AT daily dosage between PMs (median 25 mg day(-1); range 5-80) and extensive metabolizers (EMs) (median 27.5 mg day(-1); range 10-100). The (E)-10-OH-nortriptyline (NT)/dose concentrations were higher in EMs than in PMs and the NT/(E)-10-OH-NT and AT/(E)-10-OH-AT ratios were higher in PMs compared with EMs. The log sparteine metabolic ratio correlated positively with the NT/(E)-10-OH-NT ratio (r(s) = 0.821; P < 0.0005) and the AT/(E)-10-OH-AT ratio (r(s) = 0.605; P < 0.006).

Conclusion: A high proportion of CYP2D6 PMs was found in a Faroese patient group medicated with AT. However, similar doses of AT and concentrations of AT and NT were noted in EMs and PMs, probably due to varying doses and indications for AT treatment.

Figure 1

Scatter plots. (A) Correlation between the log sparteine metabolic ratio (MR) and the steady-state nortriptyline/(E)-10-hydroxynortriptyline ratio in 21 patients treated with 10–100 mg amitriptyline (AT) daily. (B) Correlation between the log sparteine MR and the steady-state amitriptyline/(E)-10-hydroxyamitriptyline ratio in 21 patients treated with 10–100 mg AT) daily. (2 functional CYP2D6 alleles, (); 1 functional CYP2D6 allele, (○); 0 functional CYP2D6 allele, (•))