Pharmacokinetics, Pharmacodynamics and Drug Metabolism
A Randomized, Quadruple Crossover Single-Blind Study on Immediate Action of Chewed and Unchewed Low-Dose Acetylsalicylic Acid Tablets in Healthy Volunteers

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Abstract

In the initial treatment of acute myocardial infarction, it is important to administer oral low-dose acetylsalicylic acid (ASA) within 10 min of arrival at the hospital. However, ASA is supplied as an enteric-coated tablet or buffered tablet to prevent gastric irritation. Although current guidelines recommended that patients should chew their initial dose of ASA, there is little evidence as to whether this is efficacious. Therefore, we aimed to make a direct comparison of the pharmacokinetics and pharmacodynamics of ASA after ingestion of intact and chewed nonenteric-coated buffered ASA tablet (NBA) and enteric-coated ASA tablet (ECA) in a quadruple crossover study in healthy volunteers. Chewing ECA accelerated tmax of ASA absorption, which became equivalent to that after ingestion of intact or chewed NBA. A significant decrease in serum thromboxane B2 was observed 20 min after ingestion of chewed ECA, or intact or chewed NBA, and inhibition of platelet aggregation was also observed within 20 min. Thus, chewing of the ECA appears to result in a similar timing of ASA action to that in the case of chewed or unchewed NBA. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:3884–3891, 2011

Section snippets

INTRODUCTION

Acetylsalicylic acid (ASA) irreversibly acetylates and inactivates platelet cyclooxygenase (COX), which catalyzes the first step in the conversion of arachidonic acid to thromboxane A2.1., 2., 3., 4., 5., 6. Thromboxane A2 stimulates platelet recruitment, activation, aggregation, and vasoconstriction. The ASA-induced inhibition lasts for the life of the platelet or about 7–10 days.7,8 At the same time, inactivation of COX in vascular endothelial cells also prevents the synthesis of

Materials

Bufferin® 81 mg tablets (NBA) and Bayaspirin® 100 mg (ECA) were purchased from Eisai Company, Ltd. (Tokyo, Japan) and Bayer Yakuhin, Ltd. (Osaka, Japan), respectively. Thromboxane EIA Kit was purchased from Cayman Chemical Company (Ann Arbor, Michigan). 2-Methylbenzoic acid and blank human serum were purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan) and Sigma–Aldrich (St Louis, Missouri), respectively. All other chemicals were commercial products of reagent grade or

Serum Concentration–Time Profiles of ASA and SA After Ingestion of Intact and Chewed NBA and ECA

Twelve healthy volunteers each received four separate oral drug administrations, that is, intact and chewed NBA and intact and chewed ECA. One volunteer withdrew in the middle of blood sampling after ingestion of intact ECA because of vascular pain owing to multiple venous punctures. Another volunteer withdrew in the middle of the intact ECA period because of feeling unwell, and also retracted her consent to participate in the period of chewed ingestion of NBA. Figures 1 and 2 illustrate the

DISCUSSION

The US Food and Drug Administration approved general ASA formulations as an antiplatelet drug in 1998. In Japan, “Baby Bufferin,” which contained 81 mg ASA at that time, and Bayaspirin® 100 mg tablet were used as off-label pharmaceuticals before 1999, when Ministry of Health, Labour and Welfare, Japan, approved their use. These approvals were not based on a new clinical trial, but were based on literature data. Indeed, the American College of Cardiology and the American Heart Association as well

CONCLUSION

Our quadruple crossover clinical trial provides pharmacokinetic and pharmacodynamic evidence to support the recommendation of the Clinical Guidelines for Acute Myocardial Infarction that the initial dose of aspirin following admission to hospital should be chewed. Chewing ECA accelerated ASA absorption and onset of antiplatelet action even in the nonfasting state. Ingestion of either intact or chewed NBA provided outcomes comparable to that after ingestion of chewed ECA.

Acknowledgements

We thank Ms. Junko Matsuo, Yukie Kitayama, Kumiko Iwatani, Misako Dai, Yuki Oohata, Teruko Kitagawa, Miyuki Ueda, Noriko Teranishi, Hiroko Maeba, Motoko Suzuki, Miyuki Muramatsu, and Yoko Konishi for their help with blood sampling. This study was supported in part by Eisai Co. Ltd.

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