Abstract
Previously we have found vicagrel, a new acetate derivative of clopidogrel, underwent hydrolysis to 2-oxo-clopidogrel and subsequent conversions to its pharmacological active metabolite (AM) and inactive carboxylic acid metabolite (CAM). This study demonstrated the interspecies differences of the vicagrel bioactivation by comparing the critical vicagrel metabolites formation in rats, dogs and human. The pharmacokinetic studies with rats and dogs were conducted after intragastric administration of vicagrel, followed by in vitro metabolism investigation in venous system, intestinal/hepatic microsomes from rats, dogs and human. An obvious disparity was observed in system exposure to AM (99.0 vs. 635.1 μg⋅h/L, p < 0.05) and CAM (10119 vs. 2634 μg⋅h/L, p < 0.05) in rats and dogs. It was shown that the cleavage of vicagrel was almost completed in intestine with great different clearance (53.28 vs. 3.643 L⋅h-1⋅kg-1, p < 0.05) in rats and dogs. With no further hydrolysis to CAM, the greatest clearance of AM (3.26 mL⋅h-1⋅kg-1) was found in dog intestine. In rat plasma, 2-oxo-clopidogrel was much more extensively hydrolyzed to CAM than in dog and human. Albeit similar hydrolysis clearance and AM production was observed among hepatic microsomes of the three species, the production velocity of CAM ranked highest in dogs (7.55 pmol/min/mg protein). Therefore, the unconformity of AM and CAM exposure cross species mainly came from the metabolism of 2-oxo-clopidogrel associated largely with tissue specificity and interspecies differences of esterases. In human, the pharmacokinetics of vicagrel might be more optimistic due to less inactivation hydrolysis before reaching liver.
Highlights
The low-response or non-response to clopidogrel treatment in cardiovascular diseases is of increasing concern, in the condition of acute coronary syndrome (ACS) or clopidogrel resistance (CR) (Nguyen et al, 2005; Vlachojannis et al, 2011; Qureshi and Hobson, 2013)
MP-active metabolite (AM) (AM derivatized with 3-methoxyphenacyl bromide) and carboxylic acid metabolite (CAM) of 2-oxo-clopidogrel was synthesized by the Center of Drug Discovery, China Pharmaceutical University
In order to compare the metabolic profiles of vicagrel or 2-oxo-clopidogrel among rats, dogs and human, we introduced the in vitro clearance, Clin vitro by scaled in organ level or the whole body in terms of kinetics, which were estimated by the following equation: C1in vitro
Summary
The low-response or non-response to clopidogrel treatment in cardiovascular diseases is of increasing concern, in the condition of acute coronary syndrome (ACS) or clopidogrel resistance (CR) (Nguyen et al, 2005; Vlachojannis et al, 2011; Qureshi and Hobson, 2013). Pre-systemic Bioactivation of Vicagrel in Species thrombotic events following percutaneous coronary intervention (PCI) (Cooke et al, 2006). Albeit this combined therapy is highly recommended for its efficiency on reducing the mortality, it showed potential gastro-intestinal risk such as duodenal ulcer and gastrointestinal bleeding caused by aspirin in the formulation (Cooke et al, 2006). A modified analog of clopidogrel shows higher pharmacological potency due to its rapid conversion to active metabolite (AM), which allows it to be used as monotherapy for the treatment of ACS (Lazar and Lincoff, 2009; Wiviott et al, 2010). Vicagrel, sharing the similar metabolic pattern to prasugrel, is esterified from clopidogrel being expected to perform improved anti-platelet efficiency and reduced bleeding risk (Shan et al, 2012)
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