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  1. Article ; Online: Impact of amiodarone use on metoprolol concentrations, α-OH-metoprolol concentrations, metoprolol dosing and heart rate: A cross-sectional study.

    Robert, Sabrina / Pilon, Marc-Olivier / Oussaïd, Essaïd / Meloche, Maxime / Leclair, Grégoire / Jutras, Martin / Gaulin, Marie-Josée / Mongrain, Ian / Busseuil, David / Tardif, Jean-Claude / Dubé, Marie-Pierre / de Denus, Simon

    Pharmacology research & perspectives

    2023  Volume 11, Issue 5, Page(s) e01137

    Abstract: Small studies suggest that amiodarone is a weak inhibitor of cytochrome P450 (CYP) 2D6. Inhibition of CYP2D6 leads to increases in concentrations of drugs metabolized by the enzyme, such as metoprolol. Considering that both metoprolol and amiodarone have ...

    Abstract Small studies suggest that amiodarone is a weak inhibitor of cytochrome P450 (CYP) 2D6. Inhibition of CYP2D6 leads to increases in concentrations of drugs metabolized by the enzyme, such as metoprolol. Considering that both metoprolol and amiodarone have β-adrenergic blocking properties and that the modest interaction between the two drugs would result in increased metoprolol concentrations, this could lead to a higher risk of bradycardia and atrioventricular block. The primary objective of this study was to evaluate whether metoprolol plasma concentrations collected at random timepoints from patients enrolled in the Montreal Heart Institute Hospital Cohort could be useful in identifying the modest pharmacokinetic interaction between amiodarone and metoprolol. We performed an analysis of a cross-sectional study, conducted as part of the Montreal Heart Institute Hospital Cohort. All participants were self-described "White" adults with metoprolol being a part of their daily pharmacotherapy regimen. Of the 999 patients being treated with metoprolol, 36 were also taking amiodarone. Amiodarone use was associated with higher metoprolol concentrations following adjustment for different covariates (p = .0132). Consistently, the association between amiodarone use and lower heart rate was apparent and significant after adjustment for all covariates under study (p = .0001). Our results highlight that single randomly collected blood samples can be leveraged to detect modest pharmacokinetic interactions.
    MeSH term(s) Adult ; Humans ; Amiodarone ; Heart Rate ; Cross-Sectional Studies ; Metoprolol ; Bradycardia ; Cytochrome P-450 CYP2D6
    Chemical Substances Amiodarone (N3RQ532IUT) ; Metoprolol (GEB06NHM23) ; Cytochrome P-450 CYP2D6 (EC 1.14.14.1)
    Language English
    Publishing date 2023-09-21
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2740389-0
    ISSN 2052-1707 ; 2052-1707
    ISSN (online) 2052-1707
    ISSN 2052-1707
    DOI 10.1002/prp2.1137
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Females present higher dose-adjusted drug concentrations of metoprolol and allopurinol/oxypurinol than males.

    Hindi, Jessica / Pilon, Marc-Olivier / Meloche, Maxime / Leclair, Grégoire / Oussaïd, Essaïd / St-Jean, Isabelle / Jutras, Martin / Gaulin, Marie-Josée / Mongrain, Ian / Busseuil, David / Rouleau, Jean Lucien / Tardif, Jean-Claude / Dubé, Marie-Pierre / de Denus, Simon

    Clinical and translational science

    2023  Volume 16, Issue 5, Page(s) 872–885

    Abstract: Females present a higher risk of adverse drug reactions. Sex-related differences in drug concentrations may contribute to these observations but they remain understudied given the underrepresentation of females in clinical trials. The aim of this study ... ...

    Abstract Females present a higher risk of adverse drug reactions. Sex-related differences in drug concentrations may contribute to these observations but they remain understudied given the underrepresentation of females in clinical trials. The aim of this study was to investigate whether anthropometric and socioeconomic factors and comorbidities could explain sex-related differences in concentrations and dosing for metoprolol and oxypurinol, the active metabolite of allopurinol. We conducted an analysis of two cross-sectional studies. Participants were self-described "White" adults taking metoprolol or allopurinol selected from the Montreal Heart Institute Hospital Cohort. A total of 1007 participants were included in the metoprolol subpopulation and 459 participants in the allopurinol subpopulation; 73% and 86% of the participants from the metoprolol and allopurinol subpopulations were males, respectively. Females presented higher age- and dose-adjusted concentrations of both metoprolol and oxypurinol (both p < 0.03). Accordingly, females presented higher unadjusted and age-adjusted concentration:dose ratio of both metoprolol and allopurinol/oxypurinol compared to males (all p < 3.0 × 10
    MeSH term(s) Male ; Female ; Animals ; Allopurinol ; Oxypurinol ; Metoprolol ; Prospective Studies ; Cross-Sectional Studies ; Dose-Response Relationship, Drug
    Chemical Substances Allopurinol (63CZ7GJN5I) ; Oxypurinol (G97OZE5068) ; Metoprolol (GEB06NHM23)
    Language English
    Publishing date 2023-03-02
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2433157-0
    ISSN 1752-8062 ; 1752-8054
    ISSN (online) 1752-8062
    ISSN 1752-8054
    DOI 10.1111/cts.13497
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: An association study of ABCG2 rs2231142 on the concentrations of allopurinol and its metabolites.

    Pilon, Marc-Olivier / Leclair, Grégoire / Oussaïd, Essaïd / St-Jean, Isabelle / Jutras, Martin / Gaulin, Marie-Josée / Mongrain, Ian / Busseuil, David / Rouleau, Jean Lucien / Tardif, Jean-Claude / Dubé, Marie-Pierre / de Denus, Simon

    Clinical and translational science

    2022  Volume 15, Issue 8, Page(s) 2024–2034

    Abstract: ABCG2 is a gene that codes for the human breast cancer resistance protein (BCRP). It is established that rs2231142 G>T, a single nucleotide polymorphism of the ABCG2 gene, is associated with gout and poor response to allopurinol, a uric acid-lowering ... ...

    Abstract ABCG2 is a gene that codes for the human breast cancer resistance protein (BCRP). It is established that rs2231142 G>T, a single nucleotide polymorphism of the ABCG2 gene, is associated with gout and poor response to allopurinol, a uric acid-lowering agent used to treat this condition. It has also been suggested that oxypurinol, the primary active metabolite of allopurinol, is a substrate of the BCRP. We thus hypothesized that carrying the rs2231142 variant would be associated with decreased oxypurinol concentrations, which would explain the lower reduction in uric acid. We performed a cross-sectional study to investigate the association between the ABCG2 rs2231142 variant and oxypurinol, allopurinol, and allopurinol riboside concentrations in 459 participants from the Montreal Heart Institute Hospital Cohort. Age, sex, weight, use of diuretics, and estimated glomerular filtration rate were all significantly associated with oxypurinol plasma concentration. No association was found between rs2231142 and oxypurinol, allopurinol and allopurinol riboside plasma concentrations. Rs2231142 was not significantly associated with daily allopurinol dose in the overall population, but an association was observed in men, with T carriers receiving higher doses. Our results do not support a major role of ABCG2 in the pharmacokinetics of allopurinol or its metabolites. The underlying mechanism of the association between rs2231142 and allopurinol efficacy requires further investigation.
    MeSH term(s) ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics ; ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism ; Allopurinol/analogs & derivatives ; Allopurinol/blood ; Allopurinol/metabolism ; Allopurinol/pharmacokinetics ; Cross-Sectional Studies ; Humans ; Oxypurinol/blood ; Oxypurinol/metabolism ; Oxypurinol/pharmacokinetics ; Ribonucleosides/blood ; Ribonucleosides/metabolism ; Ribonucleosides/pharmacokinetics ; Uric Acid/blood
    Chemical Substances ABCG2 protein, human ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; Ribonucleosides ; Uric Acid (268B43MJ25) ; Allopurinol (63CZ7GJN5I) ; Oxypurinol (G97OZE5068) ; allopurinol riboside (WZS8452SEC)
    Language English
    Publishing date 2022-06-10
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2433157-0
    ISSN 1752-8062 ; 1752-8054
    ISSN (online) 1752-8062
    ISSN 1752-8054
    DOI 10.1111/cts.13318
    Database MEDical Literature Analysis and Retrieval System OnLINE

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