Absorption Of Salicylic Acid Research Articles

Positional and Conformational Isomerism in Hydroxybenzoic Acid: A Core-Level Study and Comparison with Phenol and Benzoic Acid.

Three positional isomers of hydroxybenzoic acid, as well as phenol and benzoic acid, were studied using core-level photoemission and X-ray absorption spectroscopies, supported by quantum chemical calculations. While 2-hydroxybenzoic (salicylic) acid exists as a single conformer with an internal hydrogen bond, 3- and 4-hydroxybenzoic acids are mixtures of multiple conformers. The effects due to isomerism are clearly seen in the C 1s and O 1s photoelectron spectra, whereas the conformational effects on the binding energies are less pronounced. The O 1s photoelectron spectrum of salicylic acid is significantly different from that of the other two isomers, providing a signature of the hydrogen bond. In contrast, the oxygen K edge X-ray absorption spectra of the three hydroxybenzoic acids show only minor differences. The salicylic acid absorption spectrum at the carbon K edge shows a more resolved vibrational structure than the spectra of the other molecules, which can be explained in part by the existence of a single conformer. Our theoretical study of vibrational excitations in the lowest C 1s absorption bands of salicylic and 4-hydroxybenzoic acids indicates that the observed structure can be assigned to 0-0 lines of various electronic transitions since most of the totally symmetric vibrational modes with sufficiently large frequencies to be resolved are predicted to be inactive. Significant sensitivity of the C 1s excitations in 3-hydroxybenzoic acid to rotational conformerism was predicted but not observed due to spectral crowding.

Effects of pH on salicylic acid toxicity in terms of biomarkers determined in the marine gastropod Gibbula umbilicalis

Alterations of the physical-chemical properties of the oceans due to anthropogenic activities are, at present, one of the most concerning environmental issues studied by researchers. One of these issues is ocean acidification, mainly caused by overproduction and release of carbon dioxide (CO2) from anthropogenic sources. Another component of environmental degradation is related to the production and release of potential toxic compounds, namely active pharmaceutical ingredients, into the aquatic environment that, combined with oceanic acidification, can cause unpredictable and never before considered deleterious effects on non-target marine organisms. Regarding this issue, the hereby study used predictions of future ocean acidification to simulate realistic scenarios of environmental exposure to a common therapeutic drug, salicylic acid (SA), in the marine gastropod Gibbula umbilicalis under different pH values. This species was exposed to a range of pH values (8.2, 7.9 and 7.6), and to already reported environmentally realistic concentrations (5, 25 and 125 μg/L) of SA. To evaluate the effects of these environmental stressors, key physiological biomarkers (GSTs, CAT, TBARS, AChE and COX) and shell hardness (SH) were quantified. Results from the present study showed that CAT and GSTs activities were enhanced by SA under water acidification; increased lipid peroxidation was also observed in organisms exposed to SA in more acidic media. In addition, the hereby study demonstrated the neurotoxic effects of SA through the inhibition of AChE. Effects were also observed in terms of COX activity, showing that SA absorption may be affected by water acidification. In terms of SH, the obtained data suggest that SA may alter the physical integrity of shells of exposed organisms. It is possible to conclude that the combination of seawater acidification and exposure to toxic xenobiotics (namely to the drug SA) may be strenuous to marine communities, making aquatic biota more susceptible to xenobiotics, and consequently endangering marine life in an unpredictable extent.

HPLC analysis of in vivo intestinal absorption and oxidative metabolism of salicylic acid in the rat.

In vivo absorption and oxidative metabolism of salicylic acid in rat small intestine was studied by luminal perfusion experiment. Perfusion through the lumen of proximal jejunum with isotonic medium containing 250 μm sodium salicylate was carried out. Absorption of salicylate was measured by a validated HPLC-DAD method which was evaluated for a number of validation characteristics (specificity, repeatability and intermediate precision, limit of detection, limit of quantification, linearity and accuracy). The method was linear over the concentration range 0.5-50 μg/mL. After liquid-liquid extraction of the perfusion samples oxidative biotransformation of salicylate was also investigated by HPLC-MS. The method was linear over the concentration range 0.25-5.0 μg/mL. Two hydroxylated metabolites of salicylic acid (2,5-dihydroxybenzoic acid and 2,3-dihydroxybenzoic acid) were detected and identified. The mean recovery of extraction was 72.4% for 2,3-DHB, 72.5% for 2,5-DHB and 50.1% for salicylic acid, respectively. The methods were successfully applied to investigate jejunal absorption and oxidative metabolism of sodium salicylate in experimental animals. The methods provide analytical background for further metabolic studies of salycilates under modified physiological conditions.

Aspirin (ASA) Absorption In Rats is much Greater in Stomach vs Duodenum

It is generally believed that ASA absorption is greater in the duodenum than stomach, similar to related salicylates (Rainsford, 1984). The objective of this experiment was to evaluate the GI location and kinetics of ASA uptake in rats. ASA or saline (control, n=6/group) was intragastrically administered to fasted rats at a dose of 100 mg ASA/kg and the gastric body, antrum, and proximal duodenum were collected, extracted in acetonitrile and ASA and salicylic acid (SA) concs were examined by HPLC. The ASA conc (µg ASA/g tissue) at 15, 30 and 60 min for: the gastric body was 278 ± 46, 78 ± 9 and 104 ± 34; antrum were 308 ± 54, 95 ± 12 and 0±0; and duodenum were 34.5 ± 10.8, 6.6 ± 1.9 and 7.9 ± 2.3 respectively. The SA concentration (µg SA/g tissue) at 15, 30 and 60 minutes for: gastric body were 524 ± 33, 434 ± 35 and 236 ± 48; antrum were 572 ± 31, 433 ± 37, and 240 ± 50; and duodenum were 1,052.0 ± 125, 630 ± 75.1 and 408 ± 103, respectively. Serum ASA conc peaked at 15 min at 3.4 ± 0.5 µg/ml falling to undetectable levels thereafter, whereas serum SA reached Cmax at 15 and 30 min at 178 ± 8 µg/ml and 152 ± 22, respectively. Conclusion Significantly greater amount of ASA (>8 times) is absorbed in the stomach of rats vs duodenum at 15 and 30 min (p<0.05). In contrast, SA absorption was not significantly different in the stomach and proximal duodenum at 15 or 30 minutes. Serum ASA peaked at 15 min falling thereafter, whereas SA remained elevated at values 40-50-fold higher for at least 30 min. Thus contrary to belief that aspirin is predominately absorbed in the duodenum due to its large surface area, this data provides evidence that aspirin is predominately absorbed in the stomach, where ASA-induced GI injury predominantly occurs. Supported by NIDDK T35DK007676-21A1.

Differential effects of some natural compounds on the transdermal absorption and penetration of caffeine and salicylic acid

Many natural products have the potential to modulate the dermal penetration of topically applied drugs and chemicals. We studied the effect of five natural compounds (hydroxycitronellal, limonene 1,2-epoxide, terpinyl acetate, p-coumaric acid, transferrulic acid) and ethanol on the transdermal penetration of two marker drugs (14C-caffeine and 14C-salicylic acid) in a flow through in vitro porcine skin diffusion system. The parameters of flux, permeability, diffusivity, and percent dose absorbed/retained were calculated and compared. The dermal absorption of 14C-caffeine was significantly higher with terpinyl acetate and limonene 1,2-epoxide as compared to ethanol; while dermal absorption of 14C-salicylic acid was significantly greater with hydroxycitronellal and limonene 1,2-epoxide as compared to ethanol. A 10-fold increase in flux and permeability of caffeine with terpinyl acetate was observed while limonene increased flux of caffeine by 4-fold and permeability by 3-fold. Hydroxycitronellal and limonene increased salicylic acid’s flux and permeability over 2-fold. The other natural compounds tested did not produce statistically significant effects on dermal penetration parameters for both caffeine and salicylic acid (p≥0.05). These results emphasize the differential effects of natural substances on the transdermal penetration of hydrophilic (caffeine) and hydrophobic (salicylic acid) drugs.

Percutaneous absorption of salicylic acid – in vitro and in vivo studies

Salicylic acid (SA) has been used in pharmaceutical and cosmetic preparations for many years. Although there are a number of studies which report on the permeation characteristics of this molecule in vitro, to our knowledge the disposition of SA in vivo has not been studied in detail. In the present work we prepared a range of SA formulations with different gelling agents. Permeation of SA from the formulations was studied in vitro using conventional Franz cells and in vivo using confocal Raman spectroscopy (CRS). Selection of the gelling agent clearly influenced the efficacy of SA delivery from all formulations. It was possible to detect SA in vivo using CRS and to depth profile the molecule. A good in vitro–in vivo correlation was also found when the cumulative amounts of SA which permeated in vitro were plotted against the CRS signal in the skin. The findings provide further confidence in the application of CRS for the study of drug disposition in the skin.

Percutaneous absorption of salicylic Acid after administration of trolamine salicylate cream in rats with transcutol(®) and eucalyptus oil pre-treated skin.

This study was conducted to assess the effect of skin pre-treatment with Transcutol(®) and eucalyptus oil on systemic absorption of topical trolamine salicylate in rat. Pharmacokinetic parameters of salicylic acid following administration of trolamine salicylate on rat skin pre-treated with either Transcutol(®) or eucalyptus oil were determined using both non-compartmental and non-linear mixed effect modeling approaches and compared with those of control group. Median (% of interquartile range/median) of salicylic acid AUC0-8hr (ng/mL/hr) values in Transcutol(®) or eucalyptus oil treated rats were 2522(139%) and 58976(141%), respectively as compared to the 3023(327%) of the control group. Skin pre-treatment with eucalyptus oil could significantly decrease extravascular volume of distribution (V/F) and elimination rate constant (k) of salicylic acid. Unlike Transcutol(®), eucalyptus oil lead to enhanced transdermal absorption of trolamine salicylate through rat skin.

Measurement of Drug Concentration in the Stomach After Intragastric Administration of Drug Solution to Healthy Volunteers: Analysis of Intragastric Fluid Dynamics and Drug Absorption

To evaluate the time-profile of intragastric fluid volume in humans after intragastric administration of drug solution. Eight healthy volunteers were intragastrically administered 150mL of drug solution containing atenolol (non-absorbable marker) and salicylic acid, then, aliquots of gastric fluid (ca. 2mL) were sampled for 2h through the catheter. Rate constants for secretion and emptying of the fluid were obtained by fitting the time-course of atenolol concentration to the simple gastric fluid transit model. Absorption of salicylic acid from the stomach was estimated by comparing its gastric concentration with that of atenolol. Kinetic analysis of atenolol concentration in the stomach indicated a rapid emptying of the fluid with an average half-life of 4.2min. Steady-state intragastric fluid volume in 8 volunteers was estimated as 4-133mL with an average of 42mL. Intragastric concentration (normalized by dose) of salicylic acid was always lower than that of atenolol, showing approximately 40% of salicylic acid was absorbed from the stomach before emptying to the intestine. This study provided valuable information on intragastric fluid dynamics and gastric drug absorption in humans to establish a better in vitro-in vivo correlation in oral drug absorption.

The correlation between the in vitro and in vivo availability of salicylic acid for membrane transfer from polysorbate 20 solutions.

Abstract The presence of 1·0% w/v polysorbate 20 in solutions of salicylic acid reduces the absorption of the drug from the rat stomach. This effect is the resultant of two opposing effects of polysorbate 20 on salicylic acid absorption. Firstly, the surfactant reduces salicylic acid absorption by solubilization and secondly the surfactant tends to enhance salicylic acid absorption by an alternate unidentified effect. Knowing the magnitude of the absorption-enhancing effect the overall effect on salicylic acid absorption can be calculated using equations that describe the availability of salicylic acid for transfer across a Cellophane membrane from polysorbate solutions.

Dose-dependent effect of calcium and magnesium etidronate on salicylic acid absorption in the rat.

Disodium etidronate affected salicylic acid absorption from the rat small intestine, in-situ, when instilled into a jejunal segment for different exposure times before the salicylic acid absorption was measured. At low etidronate concentrations and short exposure times, the salicylic acid absorption rate was significantly increased compared with saline controls. At high etidronate concentrations and longer exposure times, the absorption rate was reduced. Etidronate precomplexed with calcium or magnesium ions at low concentrations still enhanced salicylic acid absorption but at high concentrations absorption of salicylic acid was close to saline controls. Intestinal mucosa exposed to high etidronate concentrations showed a progressive structural destruction but with the complexes, there was no visible alteration. It is proposed that a solubilized etidronate complex, formed either in-situ or administered as such, is responsible for enhancing salicylic acid absorption. This effect is hidden at high etidronate concentrations because of the deterioration of the mucosal surface and at high complex concentrations because these decrease the absorbing surface area and increase the viscosity of the lumen contents.

Characterization of mitomycin C-induced gastrointestinal damage: changes in the gastric absorption of drugs in rats.

The effect of mitomycin C (MMC) pre-administration intravenously on the absorption of drugs from rat stomach has been examined by means of the in-situ loop technique. 48 h after the MMC-treatment, the absorption of salicylic acid, aspirin and sulphanilic acid was not influenced but that of sulphanilamide was significantly increased compared with the control. At 96 h, a differential effect of MMC on the absorption of each drug was seen: the absorption of weakly acidic drugs was significantly decreased while that of bases and strong sulphonic acid increased. The decreased absorption of salicylic acid and aspirin correlated with the reduced gastric mucosal blood flow. At 96 h there were severe haemorrhagic lesions in the gastric mucosae. The increase in absorption of poorly absorbed drugs could be ascribed to the increased permeability of the blood-gastric epithelium barrier as was evidenced by leakage of Evans Blue.

Enhanced gastrointestinal absorption of drugs in rats pretreated with the synthetic immunomodulator, levamisole.

The effect of levamisole on drug absorption from the rat small intestine has been investigated by means of an in-situ recirculation technique. The absorption of salicylic acid, sulphanilamide and aminopyrine was significantly increased by the intraperitoneal administration of levamisole (2 mg) 1 day before the absorption studies, but there was no significant effect on absorption from the small intestine of indomethacin, bromthymol blue, sulphafurazole (sulfisoxazole), quinine, sulphanilic acid, phenol red (phenolsulfonphthalein), L-tryptophan and fluorescein isothiocyanate-dextrans. The effect of levamisole on the absorption from the small intestine of salicylic acid was marginally dose- and time-dependent, the maximal effect being observed after pretreatment with 2 mg of levamisole 1 day before the absorption studies. Sulphanilamide, similarly, was better sorbed from the small intestine and also from the stomach in the presence of levamisole. The intraperitoneal administration of levamisole may influence the absorption of some low molecular weight drugs from the gastrointestinal tract.

The use of a perfluorochemical emulsion as a vascular perfusate in drug absorption.

In-vitro simultaneous luminal and vascular perfusion using the perfluorochemical emulsion, FC-43 emulsion, as a vascular perfusate, was examined for drug absorption in rat jejunum. The intestinal membrane in this system was found to retain its normal barrier functions for drug transport, as evident from the following: (i) stable absorption clearance of tritiated water and salicylic acid at steady-state, (ii) agreement of this clearance with that by in-situ single-pass luminal perfusion, (iii) active transport of D-glucose and its inhibition by phloridzin and (iv) normal glutamate pyruvate transaminase activity in the intestinal mucosa. FC-43 emulsion gave a more normal absorption site blood flow than the usual vascular perfusate containing erythrocytes and albumin in Krebs-Henseleit bicarbonate buffer solution. Consequently, this emulsion was useful for examining the contribution of blood flow resistance toward drug absorption. The rate-limiting steps of absorption of tritiated water, antipyrine and salicylic acid were examined by perfusion using FC-43 emulsion. The absorption of tritiated water was almost completely blood flow-limited and its absorption clearance may possibly be an approximated absorption site blood flow. The contribution of blood flow resistance to total resistance for antipyrine absorption exceeded that for salicylic acid absorption.

Percutaneous absorption: in vivo experiments.

The percutaneous absorption of esters of nicotinic acid has been studied in vivo in man. The time for erythema to be produced has been measured both when the ester is applied continuously and in 'pulse' experiments when the ester is removed before the erythema develops. The results show that the erythema is produced long before steady state diffusion across the epidermis is established and the penetration of methyl nicotinate is characterized by D/l2 = 2.3 X 10(-4)s-1 where D is the diffusion coefficient and l the thickness of the barrier. Results using glycerol water mixtures in the external phase show that the route of penetration for methyl nicotinate is through the interstitial channels and not through the keratinized cells. Data for absorption from various creams and ointments (Barrett et al 1964) show that the route is independent of the nature of the external phase. Steady state data for the absorption of salicylic acid and carbinoxamine through the abdominal skin of guinea-pigs (Arita et al 1970) show that the route of penetration does not change as the experiment proceeds. Data for the absorption of other substances (Michaels et al 1975) also fit the interstitial route.

A note on perfusion with labelled compounds to determine intestinal absorption.

Abstract An in vivo perfusion technique has been adapted for the measurement of intestinal absorption of labelled compounds. Salicylic acid, labelled with 14C, in solution with or without phenylephrine or caffeine, was perfused through the ligated and cannulated small intestine in situ of the rat. Absorption was estimated from the difference in count of the solutions entering the gut and the outflow which was sampled at 10 min intervals. Some 40–45% of the acid was found to be absorbed at each of three consecutive 10 min samplings. This was lower than, but consistent with, reported results derived by chemical assay. In the presence of the other two drugs the absorption of salicylic acid increased to 70%.

Comparative studies on percutaneous absorption.

Abstract The percutaneous absorption of salicylic acid, sulphanilamide, copper acetyl-acetonate, and copper sulphate through the intact skin of rabbits and the efficiency of lard, emulsifying ointment B.P., and water in the form of a five per cent carboxymethyl cellulose gel, as carriers, is compared. Blood levels were accepted as a measure of absorption. The physico-chemical properties of the drugs seemed to dictate the amount absorbed; the influence of the base was also significant, although less so. Best absorbed was salicylic acid, next sulphanilamide, then copper acetyl-acetonate, and finally copper sulphate, although the differences were slight between the last two; lard was the best base, then emulsifying ointment, and finally water.

Relative bioavailability of salicylic acid following dermal application of a 30% salicylic acid skin peel preparation

A single-center, single-sequence, two-period crossover study was performed to compare the systemic exposure to salicylic acid (SA) following facial application of a 30% SA cosmetic skin peel formulation applied for 5 min and an oral dose of 650 mg aspirin in nine healthy male and female subjects. The mean (SD) maximum SA concentration (Cmax) was 0.81 (0.32) microg/mL and 56.4 (14.2) microg/mL. The AUC-based safety margin ratio was 50:1. A depot effect was observed during topical application of the skin peel solution as the absorption of SA continued beyond the 5-min application period. Plasma SA Cmax values were achieved from 1.4 to 3.5 h after topical application and from 0.5 to 1.5 h after oral aspirin. The plasma concentrations in the present study (30%; 5 min) were similar to that of a low concentration (2%) applied in a leave-on product to the same body surface area. In conclusion, our results suggest that the use of this SA facial peel should not pose any significant systemic health risks.

Increased Salicylate Concentrations in Urine of Human Volunteers after Consumption of Cranberry Juice

The aim of this study was to assess whether regular consumption of cranberry juice results in elevations in urinary salicylate concentrations in persons not taking salicylate drugs. Two groups of healthy female subjects (11/group) matched for age, weight, and height consumed 250 mL of either cranberry juice or a placebo solution three times a day (i.e., 750 mL/day) for 2 weeks. At weekly intervals, salicylic acid and salicyluric acid (the major urinary metabolite of salicylic acid) concentrations were determined in urine by HPLC with electrochemical detection. Concentrations of salicylic acid in plasma were also determined. Consumption of cranberry juice was associated with a marked increase (p < 0.001) of salicyluric and salicylic acids in urine within 1 week of the intervention. After 2 weeks, there was also a small but significant (p < 0.05) increase in salicylic acid in plasma. The regular consumption of cranberry juice results in the increased absorption of salicylic acid, an anti-inflammatory compound that may benefit health.

Comparison of Franz cells and microdialysis for assessing salicylic acid penetration through human skin

The purpose of the present study was to compare Franz cells (FC) and microdialysis (MD) for monitoring the skin absorption of salicylic acid (SA). The influence of pH on SA flux was also assessed by these two techniques. Excised abdominal human skin was used in the experiments. SA was dissolved in phosphate buffer solutions of pH 2, 5 and 7 (2 mg/ml). SA concentrations in the receptor FC solutions and in MD samples were assessed by high performance liquid chromatography (HPLC). The results demonstrate that the flux of SA decreased with increased pH. The profiles permeation determined by Franz cells and microdialysis were similar. However, whatever the pH, the SA flux was higher with microdialysis than with Franz cells. The results showed that SA percutaneous permeation conformed to the pH partition hypothesis. The flux of SA was different when it was determined by the two techniques. The collect of SA, by these two techniques is different. The results of the two techniques are compared and discussed.

Salicylates

Ingestion of aspirin is the most common form of salicylate poisoning. Salicylate poisoning may also result from percutaneous absorption of salicylic acid (used in keratolytic agents) and ingestion of methyl salicylate (oil of wintergreen).