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

• Published in: British journal of clinical pharmacology 2008-01, Vol.65 (1), p.134-138
• Main Authors: Halling, Jónrit, Weihe, Pál, Brosen, Kim
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; amitriptyline; Amitriptyline - metabolism; Antidepressive Agents, Tricyclic - metabolism; Biological and medical sciences; CYP2D6 polymorphism; Cytochrome P-450 CYP2D6 - genetics; Cytochrome P-450 CYP2D6 - metabolism; Denmark - epidemiology; Faroe Islands; Female; Humans; Male; Medical sciences; Middle Aged; nortriptyline; Nortriptyline - metabolism; Pharmacology. Drug treatments; Polymorphism, Genetic; Short Reports; the Faroese population
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/j.1365-2125.2007.02969.x

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The metabolisms of amitriptyline (AT) to (E)‐10‐hydroxyamitriptyline and of nortripyline (NT) to (E)‐10‐hydroxynortriptyline are catalysed by CYP2D6. • A correlation between the sparteine metabolic ratio and the NT/(E)‐10‐hydroxynortriptyline and the AT/(E)‐10‐hydroxyamitriptyline ratios, respectively, has been observed in patients in treatment with the same dose of AT or NT. • The frequency of CYP2D6 poor metabolizers (PMs) is 15% (twofold compared with other Whites) among healthy Faroese. • This frequency has not been investigated in Faroese patients in AT treatment and the consequences of the CYP2D6 PM phenotype for dose and plasma concentrations of AT and metabolites are not known in these patients. WHAT THIS STUDY ADDS • In patients treated with different daily dosages (5–100 mg) of AT a correlation between the sparteine metabolic ratio and the NT/(E)‐10‐hydroxynortriptyline and AT/(E)‐10‐hydroxyamitriptyline ratios was observed. • A high proportion (22%) of CYP2D6 PMs in a Faroese patient group medicated with AT was observed. • However, similar doses of AT and concentrations of AT and NT were noted in extensive metabolizers and in PMs. 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 (rs = 0.821; P