title: Influence of low-dose proton pump inhibitors administered concomitantly or separately on the anti-platelet function of clopidogrel.
abstract: Proton pump inhibitors (PPIs) at low doses can effectively prevent gastrointestinal bleeding due to aspirin and are widely used in Japan for gastroprotection in patients taking anti-platelet agents. We examined the influence of different PPIs at low doses administered concomitantly or separately on anti-platelet functions of clopidogrel. In 41 healthy Japanese volunteers with different CYP2C19 genotypes who took clopidogrel 75 mg in the morning alone, or with omeprazole 10 mg, esomeprazole 10 mg, lansoprazole 15 mg, or rabeprazole 10 mg, either concomitantly in the morning or separately in the evening, we measured the inhibition of platelet aggregation (IPA, %) using VerifyNow P2Y12 assay at 4 h after the last clopidogrel dose on Day 7 of each regimen. IPA by clopidogrel with rabeprazole administered at lunchtime, approximately 4 h after clopidogrel, was also measured. Mean IPAs in those concomitantly receiving omeprazole, esomeprazole, lansoprazole or rabeprazole (47.2 ± 21.1%, 43.2 ± 20.2%, 46.4 ± 18.8%, and 47.3 ± 19.2%, respectively) were significantly decreased compared with those receiving clopidogrel alone (56.0%) (all ps < 0.001). This decrease was observed when PPIs were administered separately in the evening. However, IPA by clopidogrel with rabeprazole administered at lunchtime was 51.6%, which was markedly similar to that of clopidogrel alone (p = 0.114). All tested PPIs reduce the efficacy of clopidogrel when administered concomitantly. Our preliminary data suggest that administration of rabeprazole 4 h following clopidogrel may minimize potential drug-drug interactions.
authors.affiliation: Center for Clinical Research, Hamamatsu University School of Medicine, 1-20-1, Handayama, Higashi-ku, Hamamatsu, 431-3192, Shizuoka, Japan. furuta@hama-med.ac.jp.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Furuta
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Mitsushige
authors.initials: M
authors.lastname: Sugimoto
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Chise
authors.initials: C
authors.lastname: Kodaira
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Nishino
authors.affiliation: Department of Clinical Oncology, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Mihoko
authors.initials: M
authors.lastname: Yamade
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Uotani
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Shu
authors.initials: S
authors.lastname: Sahara
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Ichikawa
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Takuma
authors.initials: T
authors.lastname: Kagami
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Moriya
authors.initials: M
authors.lastname: Iwaizumi
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Hamaya
authors.affiliation: Department of Endoscopic and Photodynamic Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Osawa
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Sugimoto
authors.affiliation: Department of Pharmacology, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umemura
mesh_terms: D000328:Adult; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007564:Japan; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D054328:Proton Pump Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D064750:Rabeprazole / Q000008:administration & dosage; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors
chemical_list: D010975:Platelet Aggregation Inhibitors; D054328:Proton Pump Inhibitors; D064750:Rabeprazole; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine
keywords: CYP2C19; Clopidogrel; Drug–drug interaction; Esomeprazole; Genotype; Lansoprazole; Omeprazole; Platelet function; Proton pump inhibitor; Rabeprazole