The use of salicylates in rheumatic diseases has been established for over 100 years. The more recent recognition of their modification of platelet and endothelial cell function has lead to their use in other areas of medicine. Aspirin (acetylsalicylic acid) is still the most commonly used salicylate. After oral administration as an aqueous solution aspirin is rapidly absorbed at the low pH of the stomach millieu. Less rapid absorption is observed with other formulations due to the rate limiting step of tablet disintegration - this latter factor being maximal in alkaline pH. The rate of aspirin absorption is dependent not only on the formulation but also on the rate of gastric emptying. Aspirin absorption follows first-order kinetics with an absorption half-life ranging from 5 to 16 minutes. Hydrolysis of aspirin to salicylic acid by nonspecific esterases occurs in the liver and, to a lesser extent, the stomach so that only 68% of the dose reaches the systemic circulation as aspirin. Both aspirin and salicylic acid are bound to serum albumin (aspirin being capable of irreversibly acetylating many proteins), and both are distributed in the synovial cavity, central nervous system, and saliva. The serum half-life of aspirin is approximately 20 minutes. The fall in aspirin concentration is associated with a rapid rise in salicylic acid concentration. Salicylic acid is renally excreted in part unchanged and the rate of elimination is influenced by urinary pH, the presence of organic acids, and the urinary flow rate. Metabolism of salicylic acid occurs through glucuronide formation (to produce salicyluric acid), and salicyl phenolic glucoronide), conjugation with glycine (to produce salicyluric acid), and oxidation to gentisic acid. The rate of formation of salicyl phenolic glucuronide and salicyluric acid are easily saturated at low salicylic acid concentrations and their formation is described by Michaelis-Menten kinetics. The other metabolic products follow first-order kinetics. The serum half-life of salicylic acid is dose-dependent; thus, the larger the dose employed, the longer it will take to reach steady-state. There is also evidence that enzyme induction of salicyluric acid formation occurs. No significant differences exist between the pharmacokinetics of the salicylates in the elderly or in children when compared with young adults. Apart from differences in free versus albumin-bound salicylate in various disease states and physiological conditions associated with low serum albumin, pharmacokinetic parameters in patients with rheumatoid arthritis, osteoarthritis, chronic renal failure or liver disease are essentially the same.(ABSTRACT TRUNCATED AT 400 WORDS)

Clinical Pharmacokinetics of the Salicylates

Mechanisms of oxidative stress.- Chemistry of dioxygen and its activated species.- Biological sources of reduced oxygen species.- Nitric oxide: Chemistry and biology.- Pro-oxidant and antioxidant effects of nitric oxide.- Oxidative damage to DNA.- Oxidation of low density lipoprotein (LDL) by cells.- Oxidative stress in clinical situation.- Free radicals and antioxidants in human diseases.- How to demonstrate the occurrence of an oxidative stress in human?.- New developments in ESP and spin-trapping.- EPR evidence of generation of superoxide anion radicals (O2*-) by irradiation of a PDT photosensitizer: Hypericin.- Nitrone spin traps as reagents for the study of oxidative modification of low density lipoproteins: Implications for atherosclerosis.- Ascorbate radical: A valuable marker of oxidative stress.- Determination of lipid peroxidation-derivated products.- Lipid hydroperoxide analysis by reverse-phase high-performance liquid chromatography with mercury cathode electrochemical detection.- Determination of primary and secondary lipid peroxidation products: Plasma lipid hydroperoxides and thiobarbituric acid reactive substances.- Measurement of low-density lipoprotein oxidation.- Evaluation of DNA damages.- Determination of 8-oxo-purines in DNA by HPLC using amperometric detection.- Measurement of one of the features of apoptosis: DNA fragmentation.- Measurement of plasma sulfhydryl and carbonyl groups as a possible indicator of protein oxidation.- Measurement of oxidized nucleobases and nucleosides in human urine by using a GC/MS assay in the selective ion monitoring mode.- Miscellaneous techniques.- Methodological and practical aspects for in vitro studies of oxidative stress on cell culture models (toxicity and protection).- Detection and production of nitric oxide.- Salicylate hydroxylation products assay as a marker of oxidative stress in man: A sensitive HPLC-electrochemical method.

Analysis of free radicals in biological systems

To resolve questions of drug actions, efficacy, and interactions for platelet-modifying agents used clinically, we have compared the relative capacities and mechanisms of aspirin, dipyridamole, sulfinpyrazone, and dazoxiben to prevent arterial thromboembolism in a baboon model. In 136 studies the agents were given twice daily by oral administration both singly and in combination. The antithrombotic efficacy of a given therapy was determined by its capacity to interrupt steady-state platelet utilization induced by thrombogenic arteriovenous cannulae. When given alone, dipyridamole and sulfinpyrazone reduced the rate at which platelets were utilized by thrombus formation in a dose-dependent manner with essentially complete interruption by dipyridamole at 10 mg/kg per d. In contrast, neither aspirin (2-100 mg/kg per d) nor dazoxiben (20-100 mg/kg per d) decreased cannula platelet consumption detectably despite the striking reduction in the capacity of platelets to produce thromboxane B2. However, aspirin, but not dazoxiben, potentiated the antithrombotic effects of dipyridamole and sulfinpyrazone in a dose-dependent fashion without changing the pharmacokinetics for any of the agents. Complete potentiation required aspirin at 20 mg/kg per d to be given with each dose of dipyridamole. Because dazoxiben's blockade of platelet thromboxane A2 production was not associated with antithrombotic potentiation, and because complete potentiation by aspirin required a dose that fully inhibited vascular production of prostaglandin I2 (PGI2), we conclude that aspirin's potentiating effect on dipyridamole is independent of PGI2 production or inhibition of thromboxane A2 formation. In addition, because frequent repeated and synchronous dosing of aspirin was necessary, aspirin's potentiating effects appear to be produced by mechanism(s) unrelated to its potent, irreversible inhibition of platelet cyclooxygenase.

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Effects of platelet-modifying drugs on arterial thromboembolism in baboons. Aspirin potentiates the antithrombotic actions of dipyridamole and sulfinpyrazone by mechanism(s) independent of platelet cyclooxygenase inhibition.

The disposition of a low dose (600 mg) of acetylsalicylic acid (ASA) and its metabolites (salicylate, salicyluric acid and salicyl glucuronides) was studied in 25 male and female patients of different ages. Plasma levels of ASA and salicylate were found to be significantly higher in the females (young and elderly), whereas plasma levels of salicyluric acid were found to be significantly higher in the elderly (male and female) groups. The higher plasma levels of ASA and salicylate in the females appear to be due to an intrinsically lower metabolic activity in that sex, while the lower clearance of salicyluric acid leads to the accumulation of that compound in the aged. No age and sex effects were found to influence the volumes of distribution of ASA, salicylate and salicyluric acid.

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The effects of age and sex on the disposition of acetylsalicylic acid and its metabolites.

Background: The pharmacology of single doses of acetylsalicylic acid (ASA) administered intravenously (250 or 500 mg) or orally (100, 300, or 500 mg) was evaluated in a randomized, placebo-controlled, crossover study. Methods: Blood and urine samples were collected before and up to 24 hours after administration of ASA in 22 healthy volunteers. Pharmacokinetic parameters and measurements of platelet aggregation were determined using validated techniques. Results: A comparison between administration routes showed that the geometric mean dosecorrected peak concentrations (C max /D) and the geometric mean dose-corrected area under the curve (AUC 0–∞ /D) were higher following intravenous administration of ASA 500 mg compared with oral administration (estimated ratios were 11.23 and 2.03, respectively). Complete inhibition of platelet aggregation was achieved within 5 minutes with both intravenous ASA doses, reflecting a rapid onset of inhibition that was not observed with oral dosing. At 5 minutes after administration, the mean reduction in arachidonic acid-induced thromboxane B 2 synthesis ex vivo was 99.3% with ASA 250 mg intravenously and 99.7% with ASA 500 mg intravenously. In exploratory analyses, thromboxane B 2 synthesis was significantly lower after intravenous versus oral ASA 500 mg (P,0.0001) at each observed time point up to the first hour after adminis tration. Concentrations of 6-keto-prostaglandin 1α at 5 and 20 minutes after dosing were also significantly lower with ASA 500 mg intravenously than with ASA 500 mg orally. Conclusion: This study demonstrates that intravenous ASA provides more rapid and consistent platelet inhibition than oral ASA within the first hour after dosing.

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Pharmacokinetics and pharmacodynamics of acetylsalicylic acid after intravenous and oral administration to healthy volunteers.

Plasma acetylsalicylic acid and salicylic acid are assayed by a specific, rapid, and sensitive high performance liquid chromatographic procedure. The plasma samples are treated with physostigmine to inhibit esterase activity that otherwise will promote enzymatic hydrolysis of acetylsalicylic acid to salicylic acid. Conditions are chosen such that the total in vitro hydrolysis of acetylsalicylic acid is minimized to less than 5%. Plasma samples are deproteinated with methylcyanide. Acetylsalicylic acid and salicylic acid are separated by elution with a mixture of methanol, acetic acid, and water on a reversed-phase octadecyl silane column and detected by ultraviolet absorption. Quantitation is achieved by measuring absolute peak heights. Recovery and repeatability studies are good. No interference was observed when 50 drugs were also present in the various plasma samples. Concentrations of acetylsalicylic acid and salicylic acid can be obtained within 20 min of receipt of the blood specimens. Pharmacokinetic parameters obtained by this method after a single oral dose of 900 mg soluble, effervescent acetylsalicylic acid in normal healthy subjects suggest that absorption, distribution, and elimination of acetylsalicylic acid are rapidly occurring events.

B E Cham

Papers

Measurement and pharmacokinetics of acetylsalicylic acid by a novel high performance liquid chromatographic assay.