Clopidogrel variability: role of plasma protein binding alterations
Article first published online: 20 MAY 2013
© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society
British Journal of Clinical Pharmacology
Volume 75, Issue 6, pages 1468–1477, June 2013
How to Cite
Ganesan, S., Williams, C., Maslen, C. L. and Cherala, G. (2013), Clopidogrel variability: role of plasma protein binding alterations. British Journal of Clinical Pharmacology, 75: 1468–1477. doi: 10.1111/bcp.12017
- Issue published online: 20 MAY 2013
- Article first published online: 20 MAY 2013
- Accepted manuscript online: 1 NOV 2012 06:37AM EST
- Manuscript Accepted: 27 OCT 2012
- Manuscript Received: 9 AUG 2012
- Medical Research Foundation of Oregon
- OHSU Oregon Clinical & Translational Research Institute. Grant Number: NIH NCRR 1 UL1 RR024120
- OSU/OHSU College of pharmacy
- inter-individual variability;
- plasma protein binding
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.
Female subjects (n = 28) with stable coronary disease who were not taking clopidogrel were recruited. Serial blood samples were collected following 300 mg 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.
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).
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.