The role of CYP2C19 in amitriptyline N-demethylation in Chinese subjects.
OBJECTIVE
To determine the role of cytochrome P(450) (CYP)2C19 in N-demethylation of amitriptyline (AT) in healthy Chinese subjects.


METHODS
One hundred and one subjects were genotyped for CYP2C19 using polymerase chain reaction-restriction fragment length polymorphism analysis. Twelve unrelated adult men (19.7+/-0.6 years, 61.8+/-3.8 kg) were chosen and orally given a single dose of 50 mg AT, and the blood samples were drawn from a forearm vein at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, and 96 h after AT administration. Plasma concentrations of AT and nortriptyline (NT) were determined using high-performance liquid chromatography with an ultraviolet detector.


RESULTS
The mean area under the plasma concentration-time curve (AUC(AT)) of CYP2C19 poor metabolizers (PMs, n=6) was significantly higher than that of CYP2C19 extensive metabolizers (EMs, n=6) (2207+/-501 ng/ml x h(-1) vs 1596+/-406 ng/ml x h(-1), P<0.05). In contrast, the mean AUC(NT(0-)(infinity)()) of PMs was significantly lower than that of EMs (294+/-70 ng/ml x h(-1) vs 684+/-130 ng/ml x h(-1), P<0.0001). Other pharmacokinetic parameters such as clearance, half-life, maximum plasma concentration, and time to peak plasma concentration showed no significant difference between PMs and EMs (0.41+/-0.12 l /h x kg(-1) vs 0.50+/-0.15 l /h x kg(-1), 25.0+/-6.2 h vs 24.1+/-4.4 h, 96+/-25 ng/ml vs 75+/-27 ng/ml, 4.0+/-1.4 h vs 3.7+/-1.5 h, respectively).


CONCLUSIONS
The genetic defects of CYP2C19 have a significant effect on AT pharmacokinetics, and CYP2C19 plays an important role in N-demethylation of AT in vivo at a clinically therapeutic dose.
Jiang
Zhi-Ping
ZP
Pharmacogenetics Research Institute, Xiang-Ya School of Medicine, Central South University, Changsha 410078, China.
Shu
Yan
Y
Chen
Xiao-Ping
XP
Huang
Song-Lin
SL
Zhu
Rong-Hua
RH
Wang
Wei
W
He
Nan
N
Zhou
Hong-Hao
HH
D000284:Administration, Oral; D000328:Adult; D000639:Amitriptyline / Q000378:metabolism / Q000493:pharmacokinetics*; D000929:Antidepressive Agents, Tricyclic / Q000378:metabolism / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000502:physiology; D002681:China / Q000208:ethnology; D002851:Chromatography, High Pressure Liquid; D065731:Cytochrome P-450 CYP2C19; D005838:Genotype; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000502:physiology; D009661:Nortriptyline / Q000097:blood; D016133:Polymerase Chain Reaction
D000929:Antidepressive Agents, Tricyclic; D000639:Amitriptyline; D009661:Nortriptyline; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19