Relationship of paroxetine disposition to metoprolol metabolic ratio and CYP2D6*10 genotype of Korean subjects.
OBJECTIVE
To evaluate the relationship between the metabolic ratio (MR) of metoprolol, CYP2D6*10B genotype, and the disposition of paroxetine in Korean subjects.


METHODS
A single 40-mg dose of paroxetine was administered orally to one poor metabolizer and 15 healthy subjects recruited from 223 Korean extensive metabolizers whose phenotypes were predetermined by use of the metoprolol MR. Genotypes were determined by allele-specific polymerase chain reaction and the GeneChip microarray technique. Pharmacokinetic parameters were estimated from plasma concentrations of paroxetine for more than 240 hours after the oral dose.


RESULTS
The oral clearance and area under the plasma concentration versus time curve (AUC) of paroxetine were best described by a nonlinear relationship with metoprolol MR at correlation coefficients of 0.82 and 0.91, respectively (P < .05). Nine extensive metabolizer who were either homozygous or heterozygous for CYP2D6*10B had significantly lower oral clearance values of paroxetine than six extensive metabolizers with CYP2D6*1/*1. The AUC of paroxetine in subjects who were homozygous for CYP2D6*10B (666.4 +/- 169.4 ng/mL x h) was significantly greater than that of subjects who were homozygous for the wild type (194.5 +/- 55.9 ng/mL x h). Unexpectedly, the average AUC of subjects who were heterozygous for CYP2D6*10B was greater with wide variation (789.8 +/- 816.9 ng/mL x h) than that of subjects who were homozygous CYP2D6*10B/*10B mainly because of two atypical subjects whose metoprolol MR was not associated with the CYP2D6*10B genotype and who showed greater AUC and lower oral clearance than subjects with homozygous CYP2D6*10B.


CONCLUSIONS
The CYP2D6 activity measured by metoprolol MR was a strong predictor of paroxetine disposition in Korean extensive metabolizers. In general, the extensive metabolizers with the CYP2D6*10B allele seemed to have higher plasma concentrations of paroxetine than extensive metabolizers with the wild-type CYP2D6 genotype. However, quantitative prediction of paroxetine disposition from the CYP2D6*10B genotype alone was not perfect because several Korean extensive metabolizers had metoprolol MRs that were not associated with the genotype.
Yoon
Y R
YR
Department of Pharmacology, Inje University College of Medicine and Clinical Pharmacology Center, Pusan Paik Hospital, Korea.
Cha
I J
IJ
Shon
J H
JH
Kim
K A
KA
Cha
Y N
YN
Jang
I J
IJ
Park
C W
CW
Shin
S G
SG
Flockhart
D A
DA
Shin
J G
JG
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D044466:Asian People / Q000235:genetics*; D016022:Case-Control Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007723:Korea; D008297:Male; D008790:Metoprolol / Q000493:pharmacokinetics*; D017374:Paroxetine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D016133:Polymerase Chain Reaction; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013565:Sympatholytics / Q000493:pharmacokinetics*
D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol; D017374:Paroxetine; D017367:Selective Serotonin Reuptake Inhibitors; D013565:Sympatholytics