Allele-specific change of concentration and functional gene dose for the prediction of steady-state serum concentrations of amitriptyline and nortriptyline in CYP2C19 and CYP2D6 extensive and intermediate metabolizers.
BACKGROUND
Recently, new polymorphisms were described in connection with intermediate and ultrarapid CYP2D6 metabolism. These may allow a much desired prediction of metabolic activity within the extensive metabolizer group. The functional consequences are still being discussed with few data available for clinical patients.


METHODS
We conducted a prospective, blinded two-center study seeking correlations between CYP2C19 (*2,*3, and *4; conventional PCR) and CYP2D6 genotypes (*1 to *10, *35, and *41; real-time and multiplex PCR) and drug concentrations (Emit and HPLC) in 50 Caucasians receiving amitriptyline (AT; 75 mg twice a day).


RESULTS
Eighteen CYP2C19 heterozygotes (*1/*2) had higher AT (P = 0.033) and lower nortriptyline (NT; P = 0.059) concentrations than 30 homozygotes (*1/*1). For CYP2D6, we calculated two new indices, i.e., the allele-specific change of concentration on identical background (ASCOC) and a quantitative functional gene dose. The ASCOC describes the change in NT concentration attributable to a mutant allele compared with the wild type. We found significantly higher concentrations for alleles *4 (95.6%; P <0.0001), *10 (63.3%; P <0.001), and *41 (39.8%; P <0.0001) but not for *2 and *35. Assigning of semiquantitative gene doses of 0, 0.5, or 1 to each allele instead of applying the current classification system (predicted phenotypes: 3 intermediate metabolizers, 46 extensive metabolizers, and 1 ultrarapid metabolizer) produced significant NT concentration differences: gene doses of 0.5 (n =3), 1 (n = 14), 1.5 (n = 11), 2 (n = 21) and 3 (n = 1; P <0.00001).


CONCLUSIONS
AT and NT concentrations can be predicted within the group of CYP2D6 extensive metabolizers. The ASCOC provides substantial advantages compared with current methods of analysis. CYP2D6 but not CYP2C19 correlates with the sum of both concentrations used to guide AT therapy.
Steimer
Werner
W
Institut für Klinische Chemie und Pathobiochemie, Technische Universität München, Munich, Germany. Steimer@KlinChem.med.TU-Muenchen.de
Zöpf
Konstanze
K
von Amelunxen
Silvia
S
Pfeiffer
Herbert
H
Bachofer
Julia
J
Popp
Johannes
J
Messner
Barbara
B
Kissling
Werner
W
Leucht
Stefan
S
D000328:Adult; D000368:Aged; D000483:Alleles; D000639:Amitriptyline / Q000008:administration & dosage / Q000097:blood*; D000929:Antidepressive Agents, Tricyclic / Q000008:administration & dosage / Q000097:blood*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000235:genetics; D003863:Depression / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D009661:Nortriptyline / Q000008:administration & dosage / Q000097:blood*; D010597:Pharmacogenetics; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D018709:Statistics, Nonparametric
D000929:Antidepressive Agents, Tricyclic; D000639:Amitriptyline; D004247:DNA; D009661:Nortriptyline; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6