Identification of cytochrome P450 isoforms involved in the metabolism of paroxetine and estimation of their importance for human paroxetine metabolism using a population-based simulator

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Identification of cytochrome P450 isoforms involved in the metabolism of paroxetine and estimation of their importance for human paroxetine metabolism using a population-based simulator. / Jornil, Jakob; Jensen, Klaus Gjervig; Larsen, Frank; Linnet, Kristian.

In: Drug Metabolism and Disposition, Vol. 38, No. 3, 2010, p. 376-85.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Jornil, J, Jensen, KG, Larsen, F & Linnet, K 2010, 'Identification of cytochrome P450 isoforms involved in the metabolism of paroxetine and estimation of their importance for human paroxetine metabolism using a population-based simulator', Drug Metabolism and Disposition, vol. 38, no. 3, pp. 376-85. https://doi.org/10.1124/dmd.109.030551

APA

Jornil, J., Jensen, K. G., Larsen, F., & Linnet, K. (2010). Identification of cytochrome P450 isoforms involved in the metabolism of paroxetine and estimation of their importance for human paroxetine metabolism using a population-based simulator. Drug Metabolism and Disposition, 38(3), 376-85. https://doi.org/10.1124/dmd.109.030551

Vancouver

Jornil J, Jensen KG, Larsen F, Linnet K. Identification of cytochrome P450 isoforms involved in the metabolism of paroxetine and estimation of their importance for human paroxetine metabolism using a population-based simulator. Drug Metabolism and Disposition. 2010;38(3):376-85. https://doi.org/10.1124/dmd.109.030551

Author

Jornil, Jakob ; Jensen, Klaus Gjervig ; Larsen, Frank ; Linnet, Kristian. / Identification of cytochrome P450 isoforms involved in the metabolism of paroxetine and estimation of their importance for human paroxetine metabolism using a population-based simulator. In: Drug Metabolism and Disposition. 2010 ; Vol. 38, No. 3. pp. 376-85.

Bibtex

@article{e91ae3d0492711df928f000ea68e967b,
title = "Identification of cytochrome P450 isoforms involved in the metabolism of paroxetine and estimation of their importance for human paroxetine metabolism using a population-based simulator",
abstract = "We identify here for the first time the low-affinity cytochrome P450 (P450) isoforms that metabolize paroxetine, using cDNA-expressed human P450s measuring substrate depletion and paroxetine-catechol (product) formation by liquid chromatography-tandem mass spectrometry. CYP1A2, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 were identified as paroxetine-catechol-forming P450 isoforms, and CYP2C19 and CYP2D6 were identified as metabolizing P450 isoforms by substrate depletion. Michaelis-Menten constants K(m) and V(max) were determined by product formation and substrate depletion. Using selective inhibitory studies and a relative activity factor approach for pooled and single-donor human liver microsomes, we confirmed involvement of the identified P450 isoforms for paroxetine-catechol formation at 1 and 20 muM paroxetine. In addition, we used the population-based simulator Simcyp to estimate the importance of the identified paroxetine-metabolizing P450 isoforms for human metabolism, taking mechanism-based inhibition into account. The amount of active hepatic CYP2D6 and CYP3A4 (not inactivated by mechanism-based inhibition) was also estimated by Simcyp. For extensive and poor metabolizers of CYP2D6, Simcyp-estimated pharmacokinetic profiles were in good agreement with those reported in published in vivo studies. Considering the kinetic parameters, inhibition results, relative activity factor calculations, and Simcyp simulations, CYP2D6 (high affinity) and CYP3A4 (low affinity) are most likely to be the major contributors to paroxetine metabolism in humans. For some individuals CYP1A2 could be of importance for paroxetine metabolism, whereas the importance of CYP2C19 and CYP3A5 is probably limited.",
author = "Jakob Jornil and Jensen, {Klaus Gjervig} and Frank Larsen and Kristian Linnet",
year = "2010",
doi = "10.1124/dmd.109.030551",
language = "English",
volume = "38",
pages = "376--85",
journal = "Drug Metabolism and Disposition",
issn = "0090-9556",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "3",

}

RIS

TY - JOUR

T1 - Identification of cytochrome P450 isoforms involved in the metabolism of paroxetine and estimation of their importance for human paroxetine metabolism using a population-based simulator

AU - Jornil, Jakob

AU - Jensen, Klaus Gjervig

AU - Larsen, Frank

AU - Linnet, Kristian

PY - 2010

Y1 - 2010

N2 - We identify here for the first time the low-affinity cytochrome P450 (P450) isoforms that metabolize paroxetine, using cDNA-expressed human P450s measuring substrate depletion and paroxetine-catechol (product) formation by liquid chromatography-tandem mass spectrometry. CYP1A2, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 were identified as paroxetine-catechol-forming P450 isoforms, and CYP2C19 and CYP2D6 were identified as metabolizing P450 isoforms by substrate depletion. Michaelis-Menten constants K(m) and V(max) were determined by product formation and substrate depletion. Using selective inhibitory studies and a relative activity factor approach for pooled and single-donor human liver microsomes, we confirmed involvement of the identified P450 isoforms for paroxetine-catechol formation at 1 and 20 muM paroxetine. In addition, we used the population-based simulator Simcyp to estimate the importance of the identified paroxetine-metabolizing P450 isoforms for human metabolism, taking mechanism-based inhibition into account. The amount of active hepatic CYP2D6 and CYP3A4 (not inactivated by mechanism-based inhibition) was also estimated by Simcyp. For extensive and poor metabolizers of CYP2D6, Simcyp-estimated pharmacokinetic profiles were in good agreement with those reported in published in vivo studies. Considering the kinetic parameters, inhibition results, relative activity factor calculations, and Simcyp simulations, CYP2D6 (high affinity) and CYP3A4 (low affinity) are most likely to be the major contributors to paroxetine metabolism in humans. For some individuals CYP1A2 could be of importance for paroxetine metabolism, whereas the importance of CYP2C19 and CYP3A5 is probably limited.

AB - We identify here for the first time the low-affinity cytochrome P450 (P450) isoforms that metabolize paroxetine, using cDNA-expressed human P450s measuring substrate depletion and paroxetine-catechol (product) formation by liquid chromatography-tandem mass spectrometry. CYP1A2, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 were identified as paroxetine-catechol-forming P450 isoforms, and CYP2C19 and CYP2D6 were identified as metabolizing P450 isoforms by substrate depletion. Michaelis-Menten constants K(m) and V(max) were determined by product formation and substrate depletion. Using selective inhibitory studies and a relative activity factor approach for pooled and single-donor human liver microsomes, we confirmed involvement of the identified P450 isoforms for paroxetine-catechol formation at 1 and 20 muM paroxetine. In addition, we used the population-based simulator Simcyp to estimate the importance of the identified paroxetine-metabolizing P450 isoforms for human metabolism, taking mechanism-based inhibition into account. The amount of active hepatic CYP2D6 and CYP3A4 (not inactivated by mechanism-based inhibition) was also estimated by Simcyp. For extensive and poor metabolizers of CYP2D6, Simcyp-estimated pharmacokinetic profiles were in good agreement with those reported in published in vivo studies. Considering the kinetic parameters, inhibition results, relative activity factor calculations, and Simcyp simulations, CYP2D6 (high affinity) and CYP3A4 (low affinity) are most likely to be the major contributors to paroxetine metabolism in humans. For some individuals CYP1A2 could be of importance for paroxetine metabolism, whereas the importance of CYP2C19 and CYP3A5 is probably limited.

U2 - 10.1124/dmd.109.030551

DO - 10.1124/dmd.109.030551

M3 - Journal article

C2 - 20007670

VL - 38

SP - 376

EP - 385

JO - Drug Metabolism and Disposition

JF - Drug Metabolism and Disposition

SN - 0090-9556

IS - 3

ER -

ID: 19278566