Clopidogrel variability: Role of plasma protein binding alterations

Shobana Ganesan, Craig Williams, Cheryl Maslen, Ganesh Cherala

    Research output: Contribution to journalArticle

    9 Citations (Scopus)

    Abstract

    Aim: The large inter-individual variability in clopidogrel response is attributed to pharmacokinetics. Although, it has been used since the late 1990s the pharmacokinetic fate of clopidogrel and its metabolites are poorly explained. The variable response to clopidogrel is believed to be multi-factorial, caused both by genetic and non-genetic factors. In this study, we examined whether the inactive metabolite can alter the plasma protein binding of the active metabolite, thus explaining the large inter-individual variability associated with clopidogrel response. Methods: Female subjects (n = 28) with stable coronary disease who were not taking clopidogrel were recruited. Serial blood samples were collected following 300mg oral dose of clopidogrel, plasma was isolated and quantified for total and free concentrations of active and inactive metabolites. Inhibition of platelet aggregation was measured using the phosphorylated vasodilator stimulated phosphoprotein (VASP) assay. Results: A significant correlation was observed between VASP and both free (r = 0.49, P <0.05) and total (r = 0.49, P <0.05) concentrations of the active metabolite. Surprisingly, we observed a significant correlation with both free (r = 0.42, P <0.05) and total (r = 0.67, P <0.001) concentrations of the inactive metabolite as well. Free fractions of the active metabolite rose with increasing protein binding of the inactive metabolite (P <0.05). Conclusions: The above in vivo data suggest that the inactive metabolite displaces the active metabolite from binding sites. Thus, the inactive metabolite might increase the free concentration of the active metabolite leading to enhanced inhibition of platelet aggregation. The plasma protein binding mechanism would offer an additional therapeutic strategy to optimize clopidogrel pharmacotherapy.

    Original languageEnglish (US)
    Pages (from-to)1468-1477
    Number of pages10
    JournalBritish Journal of Clinical Pharmacology
    Volume75
    Issue number6
    DOIs
    StatePublished - Jun 2013

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    clopidogrel
    Protein Binding
    Blood Proteins
    Platelet Aggregation
    Pharmacokinetics
    Coronary Disease

    Keywords

    • Clopidogrel
    • Inter-individual variability
    • Pharmacokinetics
    • Plasma protein binding

    ASJC Scopus subject areas

    • Pharmacology (medical)
    • Pharmacology

    Cite this

    Clopidogrel variability : Role of plasma protein binding alterations. / Ganesan, Shobana; Williams, Craig; Maslen, Cheryl; Cherala, Ganesh.

    In: British Journal of Clinical Pharmacology, Vol. 75, No. 6, 06.2013, p. 1468-1477.

    Research output: Contribution to journalArticle

    Ganesan, Shobana ; Williams, Craig ; Maslen, Cheryl ; Cherala, Ganesh. / Clopidogrel variability : Role of plasma protein binding alterations. In: British Journal of Clinical Pharmacology. 2013 ; Vol. 75, No. 6. pp. 1468-1477.
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    abstract = "Aim: The large inter-individual variability in clopidogrel response is attributed to pharmacokinetics. Although, it has been used since the late 1990s the pharmacokinetic fate of clopidogrel and its metabolites are poorly explained. The variable response to clopidogrel is believed to be multi-factorial, caused both by genetic and non-genetic factors. In this study, we examined whether the inactive metabolite can alter the plasma protein binding of the active metabolite, thus explaining the large inter-individual variability associated with clopidogrel response. Methods: Female subjects (n = 28) with stable coronary disease who were not taking clopidogrel were recruited. Serial blood samples were collected following 300mg oral dose of clopidogrel, plasma was isolated and quantified for total and free concentrations of active and inactive metabolites. Inhibition of platelet aggregation was measured using the phosphorylated vasodilator stimulated phosphoprotein (VASP) assay. Results: A significant correlation was observed between VASP and both free (r = 0.49, P <0.05) and total (r = 0.49, P <0.05) concentrations of the active metabolite. Surprisingly, we observed a significant correlation with both free (r = 0.42, P <0.05) and total (r = 0.67, P <0.001) concentrations of the inactive metabolite as well. Free fractions of the active metabolite rose with increasing protein binding of the inactive metabolite (P <0.05). Conclusions: The above in vivo data suggest that the inactive metabolite displaces the active metabolite from binding sites. Thus, the inactive metabolite might increase the free concentration of the active metabolite leading to enhanced inhibition of platelet aggregation. The plasma protein binding mechanism would offer an additional therapeutic strategy to optimize clopidogrel pharmacotherapy.",
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    AU - Ganesan, Shobana

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    AU - Maslen, Cheryl

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    N2 - Aim: The large inter-individual variability in clopidogrel response is attributed to pharmacokinetics. Although, it has been used since the late 1990s the pharmacokinetic fate of clopidogrel and its metabolites are poorly explained. The variable response to clopidogrel is believed to be multi-factorial, caused both by genetic and non-genetic factors. In this study, we examined whether the inactive metabolite can alter the plasma protein binding of the active metabolite, thus explaining the large inter-individual variability associated with clopidogrel response. Methods: Female subjects (n = 28) with stable coronary disease who were not taking clopidogrel were recruited. Serial blood samples were collected following 300mg oral dose of clopidogrel, plasma was isolated and quantified for total and free concentrations of active and inactive metabolites. Inhibition of platelet aggregation was measured using the phosphorylated vasodilator stimulated phosphoprotein (VASP) assay. Results: A significant correlation was observed between VASP and both free (r = 0.49, P <0.05) and total (r = 0.49, P <0.05) concentrations of the active metabolite. Surprisingly, we observed a significant correlation with both free (r = 0.42, P <0.05) and total (r = 0.67, P <0.001) concentrations of the inactive metabolite as well. Free fractions of the active metabolite rose with increasing protein binding of the inactive metabolite (P <0.05). Conclusions: The above in vivo data suggest that the inactive metabolite displaces the active metabolite from binding sites. Thus, the inactive metabolite might increase the free concentration of the active metabolite leading to enhanced inhibition of platelet aggregation. The plasma protein binding mechanism would offer an additional therapeutic strategy to optimize clopidogrel pharmacotherapy.

    AB - Aim: The large inter-individual variability in clopidogrel response is attributed to pharmacokinetics. Although, it has been used since the late 1990s the pharmacokinetic fate of clopidogrel and its metabolites are poorly explained. The variable response to clopidogrel is believed to be multi-factorial, caused both by genetic and non-genetic factors. In this study, we examined whether the inactive metabolite can alter the plasma protein binding of the active metabolite, thus explaining the large inter-individual variability associated with clopidogrel response. Methods: Female subjects (n = 28) with stable coronary disease who were not taking clopidogrel were recruited. Serial blood samples were collected following 300mg oral dose of clopidogrel, plasma was isolated and quantified for total and free concentrations of active and inactive metabolites. Inhibition of platelet aggregation was measured using the phosphorylated vasodilator stimulated phosphoprotein (VASP) assay. Results: A significant correlation was observed between VASP and both free (r = 0.49, P <0.05) and total (r = 0.49, P <0.05) concentrations of the active metabolite. Surprisingly, we observed a significant correlation with both free (r = 0.42, P <0.05) and total (r = 0.67, P <0.001) concentrations of the inactive metabolite as well. Free fractions of the active metabolite rose with increasing protein binding of the inactive metabolite (P <0.05). Conclusions: The above in vivo data suggest that the inactive metabolite displaces the active metabolite from binding sites. Thus, the inactive metabolite might increase the free concentration of the active metabolite leading to enhanced inhibition of platelet aggregation. The plasma protein binding mechanism would offer an additional therapeutic strategy to optimize clopidogrel pharmacotherapy.

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    KW - Pharmacokinetics

    KW - Plasma protein binding

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