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 language | English (US) |
|---|---|
| Pages (from-to) | 1468-1477 |
| Number of pages | 10 |
| Journal | British Journal of Clinical Pharmacology |
| Volume | 75 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 2013 |
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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 journal › Article
}
TY - JOUR
T1 - Clopidogrel variability
T2 - Role of plasma protein binding alterations
AU - Ganesan, Shobana
AU - Williams, Craig
AU - Maslen, Cheryl
AU - Cherala, Ganesh
PY - 2013/6
Y1 - 2013/6
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.
KW - Clopidogrel
KW - Inter-individual variability
KW - Pharmacokinetics
KW - Plasma protein binding
UR - http://www.scopus.com/inward/record.url?scp=84878118325&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84878118325&partnerID=8YFLogxK
U2 - 10.1111/bcp.12017
DO - 10.1111/bcp.12017
M3 - Article
VL - 75
SP - 1468
EP - 1477
JO - British Journal of Clinical Pharmacology
JF - British Journal of Clinical Pharmacology
SN - 0306-5251
IS - 6
ER -