title: Theoretical investigation of aspirin dosage regimen to exhibit optimal antiplatelet effects and decrease risk of upper gastrointestinal lesions.
abstract: We investigated dosage regimens for aspirin therapy in regard to antiplatelet effects in patients without gastrointestinal lesions. Findings for inhibition of biosynthesis of thromboxane B(2) (TXB(2)) and prostaglandin E(2) (PGE(2)) were simulated based on pharmacokinetic and pharmacodynamic models using an irreversible process of inhibition of cyclooxygenase-1 (COX-1) by aspirin. We found that the inhibition of biosynthesis of TXB(2) at a steady state was greater than 90% when the dose of aspirin administered exceeded 81 mg, which was considered to exhibit a sufficient antiplatelet effect. Furthermore, it was confirmed that a dose of 162 mg or more is needed to exert an immediate antiplatelet effect on the initial day of administration. On the other hand, the inhibition of biosynthesis of PGE(2) ranged from 40-90% when aspirin was administered at a dose of 10.125-324 mg. Thus, the risk of gastrointestinal lesions differed in a dosage-dependent manner. The biosynthesis inhibition of PGE(2) was calculated to be 37.9%, with that value set as the target level for prevention of gastrointestinal disorders. We also noted a difference between platelets and gastric mucosa cells in regard to the turnover rate of COX-1, and attempted to simulate the inhibition of biosynthesis of TXB(2) and PGE(2) following administration of aspirin. However, it was not possible, as the inhibition of biosynthesis of TXB(2) was greater than 90% and that of PGE(2) was less than 37.9%, even with various dosage regimens. Our findings suggest that it is difficult to determine a rational dosage regimen of aspirin to exert an antiplatelet effect without inducing gastrointestinal lesions.
authors.affiliation: Department of Clinical Evaluation of Drug Efficacy, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432–1 Horinouchi, Hachiouji, Tokyo 192–0392, Japan.
authors.forename: Haruko
authors.initials: H
authors.lastname: Yokoyama
authors.forename: Takehiro
authors.initials: T
authors.lastname: Yaguchi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Kentaro
authors.initials: K
authors.lastname: Tokuoka
authors.forename: Masayuki
authors.initials: M
authors.lastname: Watanabe
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Kitagawa
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Yamada
mesh_terms: D001095:Arachidonic Acids / Q000096:biosynthesis*; D001241:Aspirin / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005753:Gastric Mucosa / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D005767:Gastrointestinal Diseases / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D008954:Models, Biological; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D013929:Thromboxane B2 / Q000096:biosynthesis
chemical_list: D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D010975:Platelet Aggregation Inhibitors; D013929:Thromboxane B2; D051545:Cyclooxygenase 1; D015232:Dinoprostone; D001241:Aspirin