Clopidogrel variability: role of plasma protein binding alterations

• Published in: British journal of clinical pharmacology Vol. 75; no. 6; pp. 1468 - 1477
• Main Authors: Ganesan, Shobana, Williams, Craig, Maslen, Cheryl L., Cherala, Ganesh
• Format: Journal Article
• Language: English
• Published: England Blackwell Science Inc 01.06.2013
• Subjects: Aged; Aryl Hydrocarbon Hydroxylases - genetics; Blood Proteins - metabolism; Cell Adhesion Molecules - blood; Chromatography, Liquid; clopidogrel; Coronary Disease - drug therapy; Coronary Disease - metabolism; Cytochrome P-450 CYP2C19; Female; Genotyping Techniques; Humans; inter‐individual variability; Mass Spectrometry; Microfilament Proteins - blood; Middle Aged; Pharmacokinetics; Phosphoproteins - blood; plasma protein binding; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - pharmacokinetics; Platelet Function Tests; Polymorphism, Single Nucleotide; Protein Binding - drug effects; Statistics as Topic; Ticlopidine - analogs & derivatives; Ticlopidine - pharmacokinetics
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/bcp.12017

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 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. 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.