Aspirin decreases systemic exposure to clopidogrel through modulation of P-glycoprotein but does not alter its antithrombotic activity

J Oh; D Shin; K S Lim; S Lee; K-H Jung; K Chu; K S Hong; K-H Shin; J-Y Cho; S H Yoon; S C Ji; K-S Yu; H Lee; I-J Jang

doi:10.1038/clpt.2014.49

Aspirin decreases systemic exposure to clopidogrel through modulation of P-glycoprotein but does not alter its antithrombotic activity

Clin Pharmacol Ther. 2014 Jun;95(6):608-16. doi: 10.1038/clpt.2014.49. Epub 2014 Feb 24.

Authors

J Oh¹, D Shin¹, K S Lim¹, S Lee¹, K-H Jung², K Chu², K S Hong³, K-H Shin⁴, J-Y Cho¹, S H Yoon¹, S C Ji¹, K-S Yu¹, H Lee¹, I-J Jang¹

Affiliations

¹ Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea.
² Department of Neurology, Seoul National University Hospital, Seoul, Korea.
³ Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.
⁴ College of Pharmacy, Research Institute of Pharmaceutical Science, Kyungpook National University, Daegu, Korea.

PMID: 24566733
DOI: 10.1038/clpt.2014.49

Abstract

Decreased oral clopidogrel absorption caused by induction of intestinal permeability glycoprotein (P-gp) expression after aspirin administration was observed in rats. This study evaluated the effect of aspirin coadministration on the pharmacokinetics/pharmacodynamics of clopidogrel in humans. A single 75-mg dose of clopidogrel was orally administered before and after 2 and 4 weeks of once-daily 100-mg aspirin administration in 18 healthy volunteers who were recruited based on CYP2C19 and PON1 genotypes. Plasma concentrations of clopidogrel and its active metabolite, H4, and relative platelet inhibition (RPI) were determined. The P-gp microRNA miR-27a increased by up to 7.67-fold (P = 0.004) and the clopidogrel area under the concentration-time curve (AUC) decreased by 14% (P > 0.05), but the AUC of H4 remained unchanged and RPI increased by up to 15% (P = 0.002) after aspirin administration. These findings indicate low-dose aspirin coadministration may decrease clopidogrel bioavailability but does not decrease its efficacy.

Trial registration: ClinicalTrials.gov NCT01503658.

Publication types

Clinical Trial
Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / drug effects*
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
Adenosine Diphosphate / pharmacology
Adult
Area Under Curve
Aryl Hydrocarbon Hydroxylases / genetics
Aryl Hydrocarbon Hydroxylases / metabolism
Aryldialkylphosphatase / genetics
Aryldialkylphosphatase / metabolism
Aspirin / pharmacology*
Clopidogrel
Cytochrome P-450 CYP2C19
Drug Interactions
Fibrinolytic Agents / pharmacology*
Genotype
Humans
Male
Platelet Aggregation / drug effects
Platelet Aggregation Inhibitors / pharmacokinetics
Platelet Aggregation Inhibitors / pharmacology*
RNA, Messenger / biosynthesis
RNA, Messenger / genetics
Ticlopidine / analogs & derivatives*
Ticlopidine / pharmacokinetics
Ticlopidine / pharmacology

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
Fibrinolytic Agents
Platelet Aggregation Inhibitors
RNA, Messenger
Adenosine Diphosphate
Clopidogrel
Aryl Hydrocarbon Hydroxylases
CYP2C19 protein, human
Cytochrome P-450 CYP2C19
Aryldialkylphosphatase
PON1 protein, human
Ticlopidine
Aspirin

Associated data

ClinicalTrials.gov/NCT01503658