The Antiaggregating Activity of Clopidogrel Is due to a Metabolic Activation by the Hepatic Cytochrome P450-1A

Savi, Pierre; Combalbert, Jean; Gaich, C.; Mc, Rouchon; Jp, Maffrand; Berger, Yves; Jm, Herbert

doi:10.1055/s-0038-1648859

Cited by 268 publications

(186 citation statements)

References 27 publications

Supporting

Mentioning

172

Contrasting

Unclassified

Order By: Relevance

“…Antibodies against CYP2B and CYP3A enzymes had no effect on clopidogrel metabolism, whereas those against CYP1A significantly reduced the rate of metabolism. These results, together with significantly greater inhibition of platelet aggregation in rats given clopidogrel after receiving b-napthoflavone or 3-methylcholanthrene (another CYP1A inducer), supported the conclusion that CYP1A enzymes are the major enzymes involved in clopidogrel activation in the rat [Savi et al 1994].…”

Section: Studies By Sanofisupporting

confidence: 60%

Metabolic activation of clopidogrel: in vitro data provide conflicting evidence for the contributions of CYP2C19 and PON1

Polasek

Doogue

Miners

2011

Therapeutic Advances in Drug Safety

View full text Add to dashboard Cite

The recent report that clopidogrel efficacy may be more dependent on paraoxonase-1 (PON1) than on cytochrome P450 2C19 (CYP2C19) activity raises questions about the roles of these and other enzymes in clopidogrel activation. To provide insight into the emerging PON1 versus CYP2C19 debate, this commentary summarizes the clinical evidence on the pharmacokinetic determinants of clopidogrel efficacy. We then review the in vitro studies investigating the enzymes involved in clopidogrel activation, and comment on their strengths and limitations. There is agreement amongst in vitro studies regarding the involvement of CYP1A2 and CYP2B6 in the metabolism of clopidogrel to 2-oxo-clopidogrel. However, the evidence for other CYP enzymes in the first activation step (e.g. CYP2C19 and CYP3A4) is inconsistent and dependent on the in vitro test system and laboratory. All major drug metabolizing CYP enzymes are capable of converting 2-oxo-clopidogrel to sulfenic acid intermediates that subsequently form the active thiol metabolite. However, the extent of CYP involvement in this second step has been challenged, and new evidence suggests that CYP-independent hydrolytic cleavage of the thioester bond may be more important than oxidative metabolism.

show abstract

Section: Studies By Sanofisupporting

confidence: 60%

Metabolic activation of clopidogrel: in vitro data provide conflicting evidence for the contributions of CYP2C19 and PON1

Polasek

Doogue

Miners

2011

Therapeutic Advances in Drug Safety

View full text Add to dashboard Cite

show abstract

“…44 Clopidogrel itself has no antiplatelet activity and needs to be oxidated by the hepatic cytochrome P-450 system to an active metabolite. 45 Beyond the inhibition of thrombus formation, animal experimental studies suggested direct effects of clopidogrel on arterial vessels, such as a reduced intimal proliferation after arterial injury and reduced serotonin and endothelin-1-mediated contraction of vascular smooth muscle cells (Table 1). 46 -48 In vitro studies measuring the population spike amplitude in murine hippocampal slices after a hypoxic episode found that pretreatment with clopidogrel increased neuronal integrity, compared with control treatment, taken as indication of a neuroprotective capacity of clopidogrel.…”

Section: Citicolinementioning

confidence: 99%

Multifunctional Actions of Approved and Candidate Stroke Drugs

Minnerup

Schäbitz

2009

Neurotherapeutics

View full text Add to dashboard Cite

Summary: Ischemic stroke causes brain damage by multiple pathways. Previous stroke trials have demonstrated that drugs targeting one or only a few of these pathways fail to improve clinical outcome after stroke. Drugs with multimodal actions have been suggested to overcome this challenge. In this review, we describe the mechanisms of action of agents approved for secondary prevention of ischemic stroke, such as antiplatelet, antihypertensive, and lipid-lowering drugs. These drugs exhibit considerable properties beyond their classical mechanisms, including neuroprotective and neuroregenerative properties. In addition, candidate stroke drugs currently studied in clinical phase III trials are described. Among these, albumin, hematopoietic growth factors, and citicoline have been identified as promising agents with multiple mechanisms. These drugs offer hope that additional treatment options for the acute phase after a stroke will become available in the near future.

show abstract

“…To exhibit its antiaggregatory effect, clopidogrel has to undergo intestinal absorption and cytochrome P450-dependent hepatic metabolism to form an active thiol metabolite (5)(6)(7). However, only a small proportion of administered clopidogrel is metabolized by P450 (15 % of total metabolites).…”

mentioning

confidence: 99%

“…However, only a small proportion of administered clopidogrel is metabolized by P450 (15 % of total metabolites). Most of clopidogrel is hydrolyzed by esterases to an inactive carboxylic acid metabolite (SR26334) that accounts for approximately 85 % of the clopidogrel-related compounds circulating in plasma (5)(6)(7)(8).…”

mentioning

confidence: 99%

Comparative bioavailability of two oral formulations of clopidogrel: Determination of clopidogrel and its carboxylic acid metabolite (SR26334) under fasting and fed conditions in healthy subjects

Brvar¹,

Lachance²,

Lévesque³

et al. 2014

Acta Pharmaceutica

View full text Add to dashboard Cite

Clopidogrel, a thienopyridine derivative, is a potent antiplatelet drug that inhibits adenosine diphosphate (ADP)-mediated platelet activation and aggregation by selectively and irreversibly binding to platelet P2Y 12 purinergic receptor (1). Results of a large clinical trial have demonstrated an overall benefit of clopidogrel over aspirin in the prevention of vascular ischemic events (myocardial infarction, stroke, vascular death) in patients with a history of symptomatic atherosclerotic disease (2). However, platelet inhibition by clopidogrel is highly variable, and patients with reduced platelet inhibition have an increased risk of major cardiovascular events (3, 4). Two randomized, single dose, 2-period, 2-sequence crossover studies were conducted to evaluate the comparative bioavailability of two clopidogrel formulations under fasting and fed conditions. Assessment of bioequivalence was based upon measurement of plasma concentrations of the parent drug, clopidogrel, and its major (inactive) metabolite, clopidogrel carboxylic acid, using improved methanol-free extraction. Bioequivalence of Krka's formulation to the innovator's formulation was demonstrated under both fasting and fed conditions on 205 volunteers. Confidence intervals for AUC 0-t , AUC 0-inf and C max of clopidogrel and its main metabolite were well within the acceptance range of 80.00 to 125.00 %. Food substantially increased the bioavailability of clopidogrel from both formulations, while no effect of food on the extent and rate of exposure to the metabolite was observed. The effect of food was comparable between the two formulations, as indicated by the same direction and rank of food impact on the bioavailability of both formulations.

show abstract

The Antiaggregating Activity of Clopidogrel Is due to a Metabolic Activation by the Hepatic Cytochrome P450-1A

Cited by 268 publications

References 27 publications

Metabolic activation of clopidogrel: in vitro data provide conflicting evidence for the contributions of CYP2C19 and PON1

Metabolic activation of clopidogrel: in vitro data provide conflicting evidence for the contributions of CYP2C19 and PON1

Multifunctional Actions of Approved and Candidate Stroke Drugs

Comparative bioavailability of two oral formulations of clopidogrel: Determination of clopidogrel and its carboxylic acid metabolite (SR26334) under fasting and fed conditions in healthy subjects

Contact Info

Product

Resources

About