Relationship of paroxetine disposition to metoprolol metabolic ratio and CYP2D6*10 genotype of Korean subjects

Young Ran Yoon, In June Cha, Ji Hong Shon, Kyung Ah Kim, Young Nam Cha, In Jin Jang, Chan Woong Park, Sang Goo Shin, David A. Flockhart, Jae Gook Shin

Research output: Contribution to journalArticle

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Abstract

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 · h) was significantly greater than that of subjects who were homozygous for the wild type (194.5 ± 55.9 ng/mL · h). Unexpectedly, the average AUC of subjects who were heterozygous for CYP2D6*10B was greater with wide variation (789.8 ± 816.9 ng/mL · 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.

Original languageEnglish (US)
Pages (from-to)567-576
Number of pages10
JournalClinical Pharmacology and Therapeutics
Volume67
Issue number5
StatePublished - 2000
Externally publishedYes

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Cytochrome P-450 CYP2D6
Paroxetine
Metoprolol
Genotype
Area Under Curve
Alleles
Healthy Volunteers
Pharmacokinetics

ASJC Scopus subject areas

  • Pharmacology

Cite this

Yoon, Y. R., Cha, I. J., Shon, J. H., Kim, K. A., Cha, Y. N., Jang, I. J., ... Shin, J. G. (2000). Relationship of paroxetine disposition to metoprolol metabolic ratio and CYP2D6*10 genotype of Korean subjects. Clinical Pharmacology and Therapeutics, 67(5), 567-576.

Relationship of paroxetine disposition to metoprolol metabolic ratio and CYP2D6*10 genotype of Korean subjects. / Yoon, Young Ran; Cha, In June; Shon, Ji Hong; Kim, Kyung Ah; Cha, Young Nam; Jang, In Jin; Park, Chan Woong; Shin, Sang Goo; Flockhart, David A.; Shin, Jae Gook.

In: Clinical Pharmacology and Therapeutics, Vol. 67, No. 5, 2000, p. 567-576.

Research output: Contribution to journalArticle

Yoon, YR, Cha, IJ, Shon, JH, Kim, KA, Cha, YN, Jang, IJ, Park, CW, Shin, SG, Flockhart, DA & Shin, JG 2000, 'Relationship of paroxetine disposition to metoprolol metabolic ratio and CYP2D6*10 genotype of Korean subjects', Clinical Pharmacology and Therapeutics, vol. 67, no. 5, pp. 567-576.
Yoon, Young Ran ; Cha, In June ; Shon, Ji Hong ; Kim, Kyung Ah ; Cha, Young Nam ; Jang, In Jin ; Park, Chan Woong ; Shin, Sang Goo ; Flockhart, David A. ; Shin, Jae Gook. / Relationship of paroxetine disposition to metoprolol metabolic ratio and CYP2D6*10 genotype of Korean subjects. In: Clinical Pharmacology and Therapeutics. 2000 ; Vol. 67, No. 5. pp. 567-576.
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abstract = "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 · h) was significantly greater than that of subjects who were homozygous for the wild type (194.5 ± 55.9 ng/mL · h). Unexpectedly, the average AUC of subjects who were heterozygous for CYP2D6*10B was greater with wide variation (789.8 ± 816.9 ng/mL · 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.",
author = "Yoon, {Young Ran} and Cha, {In June} and Shon, {Ji Hong} and Kim, {Kyung Ah} and Cha, {Young Nam} and Jang, {In Jin} and Park, {Chan Woong} and Shin, {Sang Goo} and Flockhart, {David A.} and Shin, {Jae Gook}",
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T1 - Relationship of paroxetine disposition to metoprolol metabolic ratio and CYP2D6*10 genotype of Korean subjects

AU - Yoon, Young Ran

AU - Cha, In June

AU - Shon, Ji Hong

AU - Kim, Kyung Ah

AU - Cha, Young Nam

AU - Jang, In Jin

AU - Park, Chan Woong

AU - Shin, Sang Goo

AU - Flockhart, David A.

AU - Shin, Jae Gook

PY - 2000

Y1 - 2000

N2 - 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 · h) was significantly greater than that of subjects who were homozygous for the wild type (194.5 ± 55.9 ng/mL · h). Unexpectedly, the average AUC of subjects who were heterozygous for CYP2D6*10B was greater with wide variation (789.8 ± 816.9 ng/mL · 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.

AB - 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 · h) was significantly greater than that of subjects who were homozygous for the wild type (194.5 ± 55.9 ng/mL · h). Unexpectedly, the average AUC of subjects who were heterozygous for CYP2D6*10B was greater with wide variation (789.8 ± 816.9 ng/mL · 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.

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