Limits...
Potent and Orally Bioavailable Antiplatelet Agent, PLD-301, with the Potential of Overcoming Clopidogrel Resistance

View Article: PubMed Central - PubMed

ABSTRACT

PLD-301, a phosphate prodrug of clopidogrel thiolactone discovered by Prelude Pharmaceuticals with the aim to overcome clopidogrel resistance, was evaluated for its in vivo inhibitory effect on ADP-induced platelet aggregation in rats. The potency of PLD-301 was similar to that of prasugrel, but much higher than that of clopidogrel. The results of pharmacokinetic analysis showed that the oral bioavailability of clopidogrel thiolactone converted from PLD-301 was 4- to 5-fold higher than that of the one converted from clopidogrel, suggesting that in comparison with clopidogrel, lower doses of PLD-301 could be used clinically. In summary, PLD-301 presents a potent and orally bioavailable antiplatelet agent that might have some advantages over clopidogrel, such as overcoming clopidogrel resistance for CYP2C19-allele loss-of-function carriers, and lowering dose-related toxicity due to a much lower effective dose.

No MeSH data available.


Metabolic Pathways of Clopidogrel and PLD-301.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4997949&req=5

Figure 1: Metabolic Pathways of Clopidogrel and PLD-301.

Mentions: Clopidogrel, an oral thienopyridine-class antiplatelet agent, has been widely used to inhibit blood clots in coronary artery disease, peripheral vascular disease, and cerebrovascular disease. It is the most prescribed antiplatelet drug for the prevention of vascular events in acute coronary syndrome (ACS) patients and stent thrombosis after percutaneous coronary intervention (PCI) [1]. Clopidogrel works by irreversibly inhibiting a receptor named P2Y12, an adenosine diphosphate (ADP) chemoreceptor on platelet cell membranes [2-4]. Clopidogrel is a prodrug that requires in vivo conversion by the hepatic cytochrome P450 (CYP) system to generate an active metabolite called clopidogrel thiolactone, which is further converted to the clopidogrel active metabolite (AM) [5-7] (Fig. 1).


Potent and Orally Bioavailable Antiplatelet Agent, PLD-301, with the Potential of Overcoming Clopidogrel Resistance
Metabolic Pathways of Clopidogrel and PLD-301.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4997949&req=5

Figure 1: Metabolic Pathways of Clopidogrel and PLD-301.
Mentions: Clopidogrel, an oral thienopyridine-class antiplatelet agent, has been widely used to inhibit blood clots in coronary artery disease, peripheral vascular disease, and cerebrovascular disease. It is the most prescribed antiplatelet drug for the prevention of vascular events in acute coronary syndrome (ACS) patients and stent thrombosis after percutaneous coronary intervention (PCI) [1]. Clopidogrel works by irreversibly inhibiting a receptor named P2Y12, an adenosine diphosphate (ADP) chemoreceptor on platelet cell membranes [2-4]. Clopidogrel is a prodrug that requires in vivo conversion by the hepatic cytochrome P450 (CYP) system to generate an active metabolite called clopidogrel thiolactone, which is further converted to the clopidogrel active metabolite (AM) [5-7] (Fig. 1).

View Article: PubMed Central - PubMed

ABSTRACT

PLD-301, a phosphate prodrug of clopidogrel thiolactone discovered by Prelude Pharmaceuticals with the aim to overcome clopidogrel resistance, was evaluated for its in vivo inhibitory effect on ADP-induced platelet aggregation in rats. The potency of PLD-301 was similar to that of prasugrel, but much higher than that of clopidogrel. The results of pharmacokinetic analysis showed that the oral bioavailability of clopidogrel thiolactone converted from PLD-301 was 4- to 5-fold higher than that of the one converted from clopidogrel, suggesting that in comparison with clopidogrel, lower doses of PLD-301 could be used clinically. In summary, PLD-301 presents a potent and orally bioavailable antiplatelet agent that might have some advantages over clopidogrel, such as overcoming clopidogrel resistance for CYP2C19-allele loss-of-function carriers, and lowering dose-related toxicity due to a much lower effective dose.

No MeSH data available.