Salicylic acid elimination

Hydrolysis of aspirin in H2 0 leads to no incorporation of into the product salicylic acid, ruling out the anhydride as an intermediate and thereby excluding mechanism 1. The general acid catalysis of mechanism III can be ruled out on the basis of failure of other nucleophiles to show evidence for general acid catalysis by the neighboring carboxylic acid group. Because there is no reason to believe hydroxide should be special in this way, mechanism III is eliminated. Thus, mechanism II, general base catalysis of hydroxide-ion attack, is believed to be the correct description of the hydrolysis of aspirin. 

After oral administration, acetylsalicylic acid is rapidly and almost completely absorbed but in the intestinal mucosa it is partly deacetylated to salicylic acid, which also exhibits analgesic activity. The plasma half-life of acetylsalicylic acid is 15 min whereas that of salicylic acid, at low dosages of acetylsalicylic acid, is 2-3 h. Salicylic acid is eliminated more slowly when acetylsalicylic acid is administered at high dose rates because of saturation of the liver enzymes. The metabolites are mainly excreted via the kidney. 

Sulfur was once quite common in acne medications, but while it was effective at reducing inflammatory lesions, it caused more whiteheads and blackheads, from which the inflammatory lesions form. For this reason, it is usually combined with something like salicylic acid, or resorcinol, to eliminate the comedones. 

Sulfur is used in acne medications to treat inflamed lesions (pimples). It can cause whiteheads and blackheads (comedones) if used by itself, so it is usually combined with salicylic acid, benzoyl peroxide, or resorcinol, which eliminates comedones. 

Salicylic acid has a keratolytic effect, thus eliminating superficial pigmented keratinocytes and stimulating cells turnover. This superficial peeling allows TCA to act a low concentration to remove pigmented keratinocytes through papillary dermis (see Fig. 14.12). 

Dinitrofluorobenzene (DNFB) reacts with phenols and, which is not of interest here, with amino groups. Hydrogen fluoride is eliminated. DNFB does not react w ith carboxylic acids. Alcohols, if they react at all, form dinitrophenyl ethers very slowly. Very weakly dissociated phenolic hydroxyl groups, e.g., in salicylic acid (pK = 13.4), are inert towards DNFB. 

The elimination of acetylsalicylic acid follows first-order kinetics with the dipyridamole and aspirin combination and has a half-life of 0.33 hours. The half-life of salicylic acid is 1.71 hours. 

The change in the acid-base balance in the body also alters the urine pH, making it more acidic (Fig. 7.59). This alters the excretion dynamics of salicylate, because more salicylate becomes nonionized and so is reabsorbed from the kidney tubules into the blood stream rather than being excreted into the urine. As can be seen from the Figure 7.59, lowering the pH of the urine to 6 results in a dramatic decrease in the ionization of the salicylate. Hence, elimination from the body is reduced. 

A systematic investigation of the copper-catalyzed reaction between 2-bromobenzoic acid and the anions of 1,3-dicarbonyl compounds has established the optimum conditions for the direct arylation of the /3-dicarbonyl moiety (75T2607). The use of sodium hydride as the base and copper(I) bromide as catalyst is recommended. The absence of a protic solvent ensures that competitive attack on the bromobenzoic acid by a solvent-derived base leading to a salicylic acid is eliminated. For larger scale reactions the addition of toluene offers some practical advantages. 

The reaction between salicylic acid and acetyl chloride is an addition-elimination reaction where the hydroxyl group of salicylic acid adds to the carbonyl of acetyl chloride. This addition is followed by the elimination of hydrochloric acid as shown below. 

Figure 9.7 reports the measured COD values during the oxidation vs. treatment time at tested temperatures (70, 80, and 90°C). Comparison of the results shows the strong effect of temperature on the time required to complete the treatment due to the activation of persulfate. Moreover, the low final value of COD reached shows that the excess of persulfate used is sufficient for the complete elimination of salicylic acid. 

As the polyketide chain is built up, any of the reductions or eliminations from fatty acid biosynthesis can occur at any stage. The simple metabolite 6-methyl salicylic acid (6-MSAJ is made in the microorganism Penicillium patulum, and it could come from the same intermediate as orsellinic acid with one reduction,... 

While diclofenac and most other cyclooxygenase inhibitors act competitively (i.e., non-covalently), acetylsalicylic acid causes covalent modification of serine 530. Its effect may therefore last longer than that of a non-covalent inhibitor. Interestingly, the half-life of acetylsalicylic acid is rather short - about 15 minutes most of the drug is just hydrolysed to acetic acid and salicylic acid. However, salicylic acid itself still acts as a (competitive) inhibitor of Cox. Also, the covalent modification of Cox achieved early on will persist after elimination of acetylsalicylic acid, so that the clinical effect of this drug will outlast its elimination. 

At the branching point of chorismic acid, either anthranilic acid, the precursor of tryptophan, or prephenic acid, the precursor of phenylalanine, itself the precursor of tyrosine and dopa (3,4-dihydroxy-phenylalanine), is formed (Fig. 10). Phosphorylation at the 3-position, condensation with phosphoenolpyru-vate, and elimination of phosphoric acid yields choris-mate from shikimate. Chorismate is also the precursor of a number of simple, and very important, aromatic compounds, including salicylic acid, 4-amino-benzoic acid (PABA), a constituent of folic acid, and 2,3-dihydroxybenzoic acid, a key acylating group of enterobactin. 

Salicylate and its metabolites are rapidly and almost completely excreted in the urine by glomerular filtration and by renal tubular secretion. Passive reabsorption of salicylate occurs in the distal tubules. Salicylate elimination is saturable and characterized by Michaelis-Menton kinetics where the elimination half-life is dependent on the dose. Since the pRa of salicylic acid is 3, its renal clearance is greatly influenced by changes in urinary pH. Increasing urinary pH can significantly increase the overall salicylate elimination rate via ion trapping. 

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