Correlation of serum aspirin esterase activity and half-life of Salicylic acid

Trnavskỳ, K; Zachar, M

doi:10.1007/bf01972693

Cited by 16 publications

(11 citation statements)

References 6 publications

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“…It has been pointed out that platelet activation caused by other factors (like ADP or shear stress) remains essentially unchanged during aspirin therapy and if they dominate in platelet activation over the thromboxane generation pathway, might result in a secondary resistance against inhibition of the overall platelet function by aspirin [242,245,251]. In addition, some authors have proposed that the rate of ASA hydrolysis, and particularly its part governed by specific enzymes -aspirin-esterases (EC 3.1.1.55), may also play an important role in the pharmacokinetics of Aspirin ® [252][253][254][255][256]. Aspirin esterases-ascribed gender differences in ASA hydrolysis, as well as tissue-specific differences in the activity of these enzymes have been reported by some authors [254,255,[257][258][259], and one might expect an altered aspirin-esterase activity in various clinical states as the potential factors contributing to the altered blood platelets response to the Aspirin ® therapy.…”

Section: Aspirin Resistancementioning

confidence: 99%

Blood Platelet Reactivity and its Pharmacological Modulation in (People with) Diabetes Mellitus

Watała

2005

CPD

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Blood platelets play a crucial role in physiological haemostasis and in pathology of prothrombotic states, including atherosclerosis. In this paper, we review major factors underlying altered platelet reactivity, with special attention paid to abnormalities in platelet function in people with diabetes mellitus (DM). The overall picture of platelet abnormalities in DM, including altered adhesion and aggregation, is hypersensitivity of diabetic platelets to agonists. "Primed" diabetic platelets respond more frequently even to subthreshold stimuli, sooner become exhausted, consumed and finally hyposensitive, thus contributing to accelerated thrombopoiesis and release of 'fresh' hyperreactive platelets. In diabetes disturbed carbohydrate and lipid metabolism may lead to physicochemical changes in cell membrane dynamics, and consequently result in altered exposure of surface membrane receptors. These phenomena, together with increased fibrinogen binding, prostanoid metabolism, phosphoinositide turnover and calcium mobilisation often present in diabetic patients, contribute to enhanced risk of small vessel occlusions and accelerated development of atherothrombotic disease of coronary, cerebral and other vessels in diabetes. As platelet hypersensitivity in DM makes a major contribution to enhanced risk of thromboembolic macroangiopathy, and consequently enhanced morbidity and mortality, it validates use of antiplatelet agents in diabetic individuals. Platelet hyperreactivity may be cured with various antiplatelet drugs to a considerably large extent notwithstanding, evidence gathered from clinical and experimental surveys shows that this approach may not always be equally efficient in people with diabetes. Observations from clinical studies rather support the use of multifactorial strategy under such circumstances, like a combined therapy of aspirin plus either purinoreceptor blocker or GPIIb-IIIa antagonist.

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Section: Aspirin Resistancementioning

confidence: 99%

Blood Platelet Reactivity and its Pharmacological Modulation in (People with) Diabetes Mellitus

Watała

2005

CPD

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“…Although we originally hypothesized that aspirin would be a better substrate than salicylic acid (due to consideration of the hydrophilicity of salicylic acid), the opposite was found to be the case. The oxidation of salicylic acid is probably more relevant, in light of the known rapid hydrolysis of aspirin (Trnavsky and Zachar, 1975). …”

Section: Discussionmentioning

confidence: 99%

“…Although Charles Frederich von Gerhardt synthesized aspirin in 1853 (Gerhardt, 1853) and Felix Hoffman developed it as a drug in 1897 (Chemical Heritage Foundation, 2014), our knowledge of how aspirin is metabolized in humans is still not completely understood. The acetyl group is quickly hydrolyzed (enzymatically and non-enzymatically) after oral ingestion to form salicylic acid in the body (Trnavsky and Zachar, 1975). Humans further metabolize salicylic acid in a number of different ways (Fig.…”

Section: Introductionmentioning

confidence: 99%

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Aromatic hydroxylation of salicylic acid and aspirin by human cytochromes P450

Bojić

Sedgeman

Nagy

et al. 2015

European Journal of Pharmaceutical Sciences

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Aspirin (acetylsalicylic acid) is a well-known and widely-used analgesic. It is rapidly deacetylated to salicylic acid, which forms two hippuric acids—salicyluric acid and gentisuric acid—and two glucuronides. The oxidation of aspirin and salicylic acid has been reported with human liver microsomes, but data on individual cytochromes P450 involved in oxidation is lacking. In this study we monitored oxidation of these compounds by human liver microsomes and cytochrome P450 (P450) using UPLC with fluorescence detection. Microsomal oxidation of salicylic acid was much faster than aspirin. The two oxidation products were 2,5-dihydroxybenzoic acid (gentisic acid, documented by its UV and mass spectrum) and 2,3-dihydroxybenzoic acid. Formation of neither product was inhibited by desferrioxamine, suggesting a lack of contribution of oxygen radicals under these conditions. Although more liphophilic, aspirin was oxidized less efficiently, primarily to the 2,5-dihydroxy product. Recombinant human P450s 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 all catalyzed the 5-hydroxylation of salicylic acid. Inhibitor studies with human liver microsomes indicated that all six of the previously mentioned P450s could contribute to both the 5- and 3-hydroxylation of salicylic acid and that P450s 2A6 and 2B6 have contributions to 5-hydroxylation. Inhibitor studies indicated that the major human P450 involved in both 3- and 5-hydroxylation of salicylic acid is P450 2E1.

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“…For example, the half-life of aspirin is fifteen minutes, while the effective metabolic product of aspirin, salicylic acid, has a half-life as long as two hours. This illustrates the crucial role of a drug’s state during its metabolism and elimination [28, 29]. During enterohepatic circulation, such factors extend the in vivo metabolic route of drugs and may further prolong the half-life of certain drugs [30], while the volume of distribution (the ratio of the plasma concentration to the total quantity of a drug (L/kg)) reflects the overall ability to eliminate certain drugs [31].…”

Section: Introductionmentioning

confidence: 99%

The Use of Gene Ontology Term and KEGG Pathway Enrichment for Analysis of Drug Half-Life

et al. 2016

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A drug’s biological half-life is defined as the time required for the human body to metabolize or eliminate 50% of the initial drug dosage. Correctly measuring the half-life of a given drug is helpful for the safe and accurate usage of the drug. In this study, we investigated which gene ontology (GO) terms and biological pathways were highly related to the determination of drug half-life. The investigated drugs, with known half-lives, were analyzed based on their enrichment scores for associated GO terms and KEGG pathways. These scores indicate which GO terms or KEGG pathways the drug targets. The feature selection method, minimum redundancy maximum relevance, was used to analyze these GO terms and KEGG pathways and to identify important GO terms and pathways, such as sodium-independent organic anion transmembrane transporter activity (GO:0015347), monoamine transmembrane transporter activity (GO:0008504), negative regulation of synaptic transmission (GO:0050805), neuroactive ligand-receptor interaction (hsa04080), serotonergic synapse (hsa04726), and linoleic acid metabolism (hsa00591), among others. This analysis confirmed our results and may show evidence for a new method in studying drug half-lives and building effective computational methods for the prediction of drug half-lives.

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Correlation of serum aspirin esterase activity and half-life of Salicylic acid

Cited by 16 publications

References 6 publications

Blood Platelet Reactivity and its Pharmacological Modulation in (People with) Diabetes Mellitus

Blood Platelet Reactivity and its Pharmacological Modulation in (People with) Diabetes Mellitus

Aromatic hydroxylation of salicylic acid and aspirin by human cytochromes P450

The Use of Gene Ontology Term and KEGG Pathway Enrichment for Analysis of Drug Half-Life

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