Presystemic acetylation of platelets by aspirin: Reduction in rate of drug delivery to improve biochemical selectivity for thromboxane A2

G. A. Fitzgerald, M. Lupinetti, S. A. Charman, W. N. Charman

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The utility of aspirin in the treatment of vascular occlusive disease has been ascribed to its blockade of platelet thromboxane A2 (TxA2), a potent inhibitor of vascular smooth muscle contraction and platelet aggregation. Coincident with the inhibition of TxA2 by aspirin at currently used dose regimens is a decrease in formation of prostacyclin (PGI2), an eicosanoid with opposing effects to TxA2 in vivo. The coincident inhibition of PGI2 could potentially limit the therapeutic efficacy of aspirin. This study addressed the issue as to whether a reduction in the rate of drug delivery could enhance the biochemical selectivity of aspirin toward inhibition of TxA2. Intubation studies were performed in parallel groups of healthy volunteers in which a 50-mg aspirin dose was administered as either a bolus or a 5 or 10 mg/hr infusion via a nasogastric tube. A control group received buffer solution. Systemic plasma levels of aspirin, major urinary metabolites of TxA2 and PGI2 and serum thromboxane B2 levels ex vivo were evaluated. Relative to the group receiving bolus aspirin, the slower rates of aspirin delivery increased the effective selectivity of the administered aspirin for TxA2. To investigate further this apparent selectivity, controlled release (CR) dose forms of aspirin were prepared and evaluated in a preliminary dose-ranging study in healthy subjects. The doses studied were 50 and 75 mg CR and a 75-mg aspirin solution. The CR aspirin dose forms decreased the maximal plasma concentration of aspirin relative to a bolus dose. The pharmacodynamic effects of the CR formulations were assessed via measurement of ex vivo serum thromboxane B2 formation. The CR formulations depressed serum thromboxane B2 formation relative to control and the extent of depression was dose dependent. Although slower in onset with the CR preparation, the depression of serum thromboxane B2 formation was similar between the groups receiving either the 75-mg solution or CR aspirin formulations during chronic dosing. These data indicate that a reduction in the delivery rate of aspirin may enhance the biochemical selectivity for TxA2.

Original languageEnglish
Pages (from-to)1043-1049
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
Publication statusPublished - 1991
Externally publishedYes

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