Abstract
Concurrent administration of two drugs may complicate the management of acute coronary syndromes: competitive drug displacement diminishes drug binding and alters drug pharmacodynamics. We investigated the interaction of two antiplatelet compounds (PSB 0777 and cangrelor) with human serum albumin (HSA) to determine whether they compete with one another for the binding to albumin. Both examined compounds have been earlier claimed to bind to HSA (PSB 0777) or plasma proteins (cangrelor). Fluorescence spectroscopy, surface plasmon resonance spectroscopy and molecular modeling indicated that PSB 0777 and cangrelor interacted with HSA with moderate affinity (KD∼10−5 M). The binding of cangrelor to HSA involved primarily hydrophobic interactions, while the interaction of PSB 0777 with HSA was driven by hydrophobic and electrostatic forces. It was found that PSB 0777 and cangrelor do not share the same binding site on the protein. Our findings highlight the importance of albumin in the transport of PSB 0777 and cangrelor and suggest that the antiplatelet activity of the examined compounds used in combination is not affected by competition-induced changes in drug binding to HSA.
Highlights
The binding to plasma proteins is a complex and dynamic process which can profoundly influence the pharmacokinetics and pharmacodynamics of a drug
We hypothesized that two compounds with antiplatelet activity, PSB 0777 and cangrelor (P2Y12 receptor inhibitor, an adenosine triphosphate analogue), compete with each other for binding on human serum albumin, providing the additional, non-receptor mechanism underlying the effectiveness of a combined antiplatelet therapy
Our results indicate that: 1) both cangrelor and PSB 0777 bind to Human serum albumin (HSA) with moderate affinities and their antiplatelet actions are significantly decreased in the presence of plasma or HSA, 2) cangrelor binds to Sudlow site I in subdomain IIA, whereas the binding site of PSB 0777 on HSA is most likely located within subdomain IIIA in Sudlow site II, 3) cangrelor and PSB 0777 do not compete for the same binding site on HSA, as far as their binding sites on the protein are different
Summary
The binding to plasma proteins is a complex and dynamic process which can profoundly influence the pharmacokinetics and pharmacodynamics of a drug. Such binding is explained by the free drug theory, according to which only unbound drugs can cross cell membranes and exert pharmacologic effects. Albumin holds great promise as a nanocarrier system for targeted drug delivery, in particular for the transport of anti-cancer drugs (Lamichhane and Lee, 2020; Mokaberi et al, 2020; Sharifi-Rad et al, 2020). Two commonly known site markers of Sudlow site I and II are warfarin and ibuprofen, and these are applied in the competitive studies for identification of drug binding sites on HSA (Fanali et al, 2012; Graciani and Ximenes, 2013; Poor et al, 2015)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
