Clopidogrel but Not Prasugrel Significantly Inhibits the CYP2C8-Mediated Metabolism of Montelukast in Humans.

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

Kuvaus

The oxidation of montelukast is mainly mediated by cytochrome P450 (CYP) 2C8, but other mechanisms may contribute to its disposition. In healthy volunteers, we investigated the effects of two widely used P2Y(12) inhibitors on montelukast pharmacokinetics. Clopidogrel (300mg on day 1 and 75mg on day 2) increased the area under the plasma concentration-time curve (AUC) of montelukast 2.0-fold (90% confidence interval (CI) 1.72-2.28, P <0.001) and decreased the M6:montelukast AUC(0-7h) ratio to 45% of control (90% CI 40-50%, P <0.001). Prasugrel (60mg on day 1 and 10mg on day 2) had no clinically meaningful effect on montelukast pharmacokinetics. Our results imply that clopidogrel is at least a moderate inhibitor of CYP2C8, but prasugrel is not a clinically relevant CYP2C8 inhibitor. The different interaction potentials of clopidogrel and prasugrel are important to consider when antiplatelet therapy is planned for patients at risk for polypharmacy with CYP2C8 substrates.

Alkuperäiskielienglanti
LehtiClinical Pharmacology and Therapeutics
Vuosikerta104
Numero3
Sivut495-504
Sivumäärä10
ISSN0009-9236
DOI - pysyväislinkit
TilaJulkaistu - syyskuuta 2018
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

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  • 3121 Sisätaudit

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@article{4a607f7288ee43d8b829bdf07efc2d2d,
title = "Clopidogrel but Not Prasugrel Significantly Inhibits the CYP2C8-Mediated Metabolism of Montelukast in Humans.",
abstract = "The oxidation of montelukast is mainly mediated by cytochrome P450 (CYP) 2C8, but other mechanisms may contribute to its disposition. In healthy volunteers, we investigated the effects of two widely used P2Y(12) inhibitors on montelukast pharmacokinetics. Clopidogrel (300mg on day 1 and 75mg on day 2) increased the area under the plasma concentration-time curve (AUC) of montelukast 2.0-fold (90{\%} confidence interval (CI) 1.72-2.28, P <0.001) and decreased the M6:montelukast AUC(0-7h) ratio to 45{\%} of control (90{\%} CI 40-50{\%}, P <0.001). Prasugrel (60mg on day 1 and 10mg on day 2) had no clinically meaningful effect on montelukast pharmacokinetics. Our results imply that clopidogrel is at least a moderate inhibitor of CYP2C8, but prasugrel is not a clinically relevant CYP2C8 inhibitor. The different interaction potentials of clopidogrel and prasugrel are important to consider when antiplatelet therapy is planned for patients at risk for polypharmacy with CYP2C8 substrates.",
keywords = "ACUTE CORONARY SYNDROMES, CYP2C8 SUBSTRATE PIOGLITAZONE, DRUG-DRUG INTERACTIONS, GEMFIBROZIL, LEUKOTRIENE-RECEPTOR ANTAGONIST, MARKEDLY INCREASES, PHARMACOKINETICS, PLASMA-CONCENTRATIONS, 3121 Internal medicine",
author = "Itkonen, {Matti K.} and Aleksi Tornio and Filppula, {Anne M.} and Mikko Neuvonen and Neuvonen, {Pertti J.} and Mikko Niemi and Backman, {Janne T.}",
year = "2018",
month = "9",
doi = "10.1002/cpt.947",
language = "English",
volume = "104",
pages = "495--504",
journal = "Clinical Pharmacology and Therapeutics",
issn = "0009-9236",
publisher = "Wiley",
number = "3",

}

TY - JOUR

T1 - Clopidogrel but Not Prasugrel Significantly Inhibits the CYP2C8-Mediated Metabolism of Montelukast in Humans.

AU - Itkonen, Matti K.

AU - Tornio, Aleksi

AU - Filppula, Anne M.

AU - Neuvonen, Mikko

AU - Neuvonen, Pertti J.

AU - Niemi, Mikko

AU - Backman, Janne T.

PY - 2018/9

Y1 - 2018/9

N2 - The oxidation of montelukast is mainly mediated by cytochrome P450 (CYP) 2C8, but other mechanisms may contribute to its disposition. In healthy volunteers, we investigated the effects of two widely used P2Y(12) inhibitors on montelukast pharmacokinetics. Clopidogrel (300mg on day 1 and 75mg on day 2) increased the area under the plasma concentration-time curve (AUC) of montelukast 2.0-fold (90% confidence interval (CI) 1.72-2.28, P <0.001) and decreased the M6:montelukast AUC(0-7h) ratio to 45% of control (90% CI 40-50%, P <0.001). Prasugrel (60mg on day 1 and 10mg on day 2) had no clinically meaningful effect on montelukast pharmacokinetics. Our results imply that clopidogrel is at least a moderate inhibitor of CYP2C8, but prasugrel is not a clinically relevant CYP2C8 inhibitor. The different interaction potentials of clopidogrel and prasugrel are important to consider when antiplatelet therapy is planned for patients at risk for polypharmacy with CYP2C8 substrates.

AB - The oxidation of montelukast is mainly mediated by cytochrome P450 (CYP) 2C8, but other mechanisms may contribute to its disposition. In healthy volunteers, we investigated the effects of two widely used P2Y(12) inhibitors on montelukast pharmacokinetics. Clopidogrel (300mg on day 1 and 75mg on day 2) increased the area under the plasma concentration-time curve (AUC) of montelukast 2.0-fold (90% confidence interval (CI) 1.72-2.28, P <0.001) and decreased the M6:montelukast AUC(0-7h) ratio to 45% of control (90% CI 40-50%, P <0.001). Prasugrel (60mg on day 1 and 10mg on day 2) had no clinically meaningful effect on montelukast pharmacokinetics. Our results imply that clopidogrel is at least a moderate inhibitor of CYP2C8, but prasugrel is not a clinically relevant CYP2C8 inhibitor. The different interaction potentials of clopidogrel and prasugrel are important to consider when antiplatelet therapy is planned for patients at risk for polypharmacy with CYP2C8 substrates.

KW - ACUTE CORONARY SYNDROMES

KW - CYP2C8 SUBSTRATE PIOGLITAZONE

KW - DRUG-DRUG INTERACTIONS

KW - GEMFIBROZIL

KW - LEUKOTRIENE-RECEPTOR ANTAGONIST

KW - MARKEDLY INCREASES

KW - PHARMACOKINETICS

KW - PLASMA-CONCENTRATIONS

KW - 3121 Internal medicine

U2 - 10.1002/cpt.947

DO - 10.1002/cpt.947

M3 - Article

VL - 104

SP - 495

EP - 504

JO - Clinical Pharmacology and Therapeutics

JF - Clinical Pharmacology and Therapeutics

SN - 0009-9236

IS - 3

ER -