Salicylate Absorption Research Articles

Experimental and theoretical investigation of the molecular, electronic structure and solvatochromism of phenyl salicylate: External electric field effect on the electronic structure

The UV–vis absorption and steady state fluorescence spectra of phenyl salicylate (abbreviated as PS) have been recorded in a series of non-polar, polar protic and polar aprotic solvents at room temperature and the obtained spectral data are used to determine the solvatochromic behavior and the ground and excited state dipole moments. Basis set sensitive molecular structure along with X-ray crystal data are evaluated. The ground state and excited state dipole moments are determined by using Lippert-Mataga, Bakhshiev, Bilot-Kawski and Reichardt solvatochromic shift methods as a function of dielectric constant (ε) and refractive index (n) of the solvents. The larger excited state dipole moment value indicates the more polar PS in the excited state. The rate of μe/μg is found as 2.4239. Solvatochromic behavior of PS is enlightened by using Kamlet-Taft and Catalan models. Kamlet-Taft solvatochromic model indicates that non-specific solute solvent interactions are controlled by solvent dispersion-induction forces and specific interactions are directed by hydrogen-bond donor capacity of solvent. Catalan solvatochromic model designates that solute-solvent interactions are governed by solvent polarizability. Ground and excited state dipole moments are found theoretically by using DFT/B3LYP/6–311++G(d, p) and TDDFT/B3LYP/6–31++G(d, p) methods. External electric field effect on LUMO-HOMO band gap and dipole moment have been investigated by using B3LYP/6–311++G(d, p) method.

Mechanistic Evaluation of Hydration Effects on the Human Epidermal Permeation of Salicylate Esters.

We sought to understand when and how hydration enhances the percutaneous absorption of salicylate esters. Human epidermal membrane fluxes and stratum corneum solubilities of neat and diluted solutions of three esters were determined under hydrated and dehydrated conditions. Hydration doubled the human epidermal flux seen for methyl and ethyl salicylate under dehydrated conditions and increased the flux of neat glycol salicylate 10-fold. Mechanistic analyses showed that this hydration-induced enhancement arises mainly from an increase in the stratum corneum diffusivity of the three esters. Further, we showed that unlike methyl and ethyl salicylate, glycol salicylate is hygroscopic and the ∼10-fold hydration-induced flux enhancement seen with neat glycol salicylate may be due to its ability to hydrate the stratum corneum to a greater extent. The hydration-induced enhancements in in vitro epidermal flux seen here for glycol and ethyl salicylate were similar to those reported for their percutaneous absorption rates in a comparable in vivo study, whilst somewhat higher enhancement was seen for methyl salicylate in vivo. This may be explained by a physiologically induced self enhancement of neat methyl salicylate absorption in vivo which is not applicable in vitro.

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.

Absorption of salicylate powders versus tablets following overdose: a poison center observational study

Background: Salicylate absorption following overdose of aspirin (ASA) tablet formulations can be prolonged for greater than 24 h. Accordingly, serial serum concentrations are typically recommended to guide treatment. However, there are little published data on absorption following ingestion of powder ASA formulations, and it is not known if delayed ASA absorption occurs following overdose of powder formulations. The objective of this study is to compare the absorption characteristics of powder and tablet formulations of ASA in patients reported to a single poison center.Methods: Electronic records from an accredited poison center were searched for single substance acute or acute on chronic ingestions of ASA in powder form between 1 January 2002 and 31 January 2014. An identical search for ingestions of ASA tablet products between 1 January 2012 and 31 December 2013 was undertaken as the comparator group. Other inclusion criteria were age >12 years, documented time of ingestion, treatment in a health care facility within nine hours of ingestion and at least two detectable serum salicylate concentrations.Results: 16 of 25 powder and 22 of 49 tablet cases met inclusion criteria for analysis. Repeat serum salicylate concentrations following ingestion of tablets increased or insignificantly changed in 11 of 22 (50%) cases, and median serum salicylate concentrations in followed cases remained elevated for up to 12 h in some cases. In comparison, serum salicylate concentrations following powder ingestions declined in 15 of 16 (94%) cases. One patient, who ingested a powder product, underwent hemodialysis pursuant to an initial serum salicylate concentration of 96 mg/dL.Conclusions: In contrast to persistent concentrations following overdose of tablets, the majority of serum salicylate concentrations declined following ingestion of powder formulations. In this small study population, these findings suggest that prolonged absorption is unlikely following ingestions of ASA powders.

Preliminary evaluation of military, commercial and novel skin decontamination products against a chemical warfare agent simulant (methyl salicylate)

Rapid decontamination is vital to alleviate adverse health effects following dermal exposure to hazardous materials. There is an abundance of materials and products which can be utilised to remove hazardous materials from the skin. In this study, a total of 15 products were evaluated, 10 of which were commercial or military products and five were novel (molecular imprinted) polymers. The efficacies of these products were evaluated against a 10 µl droplet of 14C-methyl salicylate applied to the surface of porcine skin mounted on static diffusion cells. The current UK military decontaminant (Fuller’s earth) performed well, retaining 83% of the dose over 24 h and served as a benchmark to compare with the other test products. The five most effective test products were Fuller’s earth (the current UK military decontaminant), Fast-Act® and three novel polymers [based on itaconic acid, 2-trifluoromethylacrylic acid and N,N-methylenebis(acrylamide)]. Five products (medical moist-free wipes, 5% FloraFree™ solution, normal baby wipes, baby wipes for sensitive skin and Diphotérine™) enhanced the dermal absorption of 14C-methyl salicylate. Further work is required to establish the performance of the most effective products identified in this study against chemical warfare agents.

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.

The influence of perfusion rate on salicylate absorption in the rat.

The influence of perfusion rate on salicylate absorption in the rat.

Facilitated Percutaneous Absorption of Sodium Salicylate

Facilitated Percutaneous Absorption of Sodium Salicylate

Percutaneous Absorption of Methyl Salicylate from Polyethylene Glycol Vehicles

Percutaneous Absorption of Methyl Salicylate from Polyethylene Glycol Vehicles

Percutaneous absorption of salicylates from some commercially available topical products containing methyl salicylate or salicylate salts in rats.

Studies to determine the extent of local tissue penetration of topically applied, commercially available salicylate esters and salts were conducted in male Wistar rats. The salicylate concentration in plasma, tissues underlying the site of drug application, and similar tissues on the contralateral (control) side were measured. The plasma and tissue salicylate levels suggest that direct penetration of salicylate was predominant to the top muscle level on the treated site. Results also suggest that the drugs were first absorbed into the bloodstream and subsequently distributed to both the deeper tissues on the treated site and the contralateral tissues. The topical application of formulations of ester methyl salicylate and salts triethanolamine salicylate and diethylamine salicylate containing comparable salicylate concentrations yielded similar salicylate concentrations in the various tissues. The salicylate concentrations in the deeper tissues approached concentrations observed in the contralateral tissues suggesting that salicylate present in these tissues was due to the systemic blood supply.

Effect of molecular weight on the dermatopharmacokinetics and systemic disposition of drugs after intracutaneous injection

The aim of this study was to investigate the effect of molecular weight on the topical migration and systemic absorption of drugs, sodium salicylate (SA), calcein sodium (CAL) and FITC-dextrans (FD-4, FD-10, FD-20 and FD-40), after intracutaneous ( i.c.) injection. The apparent diffusion coefficients in the skin ( D s) of SA, CAL and FD-4 after i.c. injection were almost the same and slightly less than 1 × 10 −4 cm 2/min. The D s value drastically decreased with molecular weight more than 10 kDa. The plasma concentration–time curve after i.c. injection was predicted by the convolution method. The ratio of AUC (observed/predicted) was approximately unity for SA, CAL and FD-4 although the systemic absorption of only FD-4 was delayed. In contrast, the AUC ratios of FD-10, FD-20 and FD-40 were about 0.5, 0.2 and 0.06, respectively, and obviously decreased with the molecular weight. The elimination of FD-10, FD-20 and FD-40 from the skin was slow and the drugs tended to remain in the muscle. These results indicated the importance of diffusion in the skin and permeability through the blood vessels for local migration and systemic absorption of drugs after penetration into viable skin.

In Vitro Dermal Absorption of Methyl Salicylate, Ethyl Parathion, and Malathion: First Responder Safety

In vitro tests with fresh dermatomed (0.3 to 0.4 mm thick) female breast skin and one leg skin specimen were conducted in Bronaugh flow-through Teflon diffusion cells with three chemicals used to simulate chemical warfare agents: 14C-radiolabeled methyl salicylate (MES), ethyl parathion (PT), and malathion (MT), at three dose levels (2, 20, and 200 mM). Tests were conducted at a skin temperature of 29°C using a brief 30-min exposure to the chemical and a 6.5-h receivor collection period. Rapid absorption of all three chemicals was observed, with MES absorbed about 10-fold faster than PT and MT. For MES, PT, and MT, respectively, there was 32%, 7%, and 12% absorption into the receivor solution (Hank's HEPES buffered saline with 4% bovine serum albumin [BSA], pH 7.4) at the low dose (2 mM), 17%, 2%, and 3% at the medium dose (20 mM), and 11%, 1%, and 1% at the high dose (200 mM) levels. Including the skin depot for MES, PT, and MT, respectively, there was 40%, 41%, and 21% (low dose), 26%, 16%, and 8% (medium dose), and 13%, 19%, and 10% (high does) absorption. Efficacy of skin soap washing conducted at the 30 min exposure time ranged from 31% to 86%, varying by chemical and dose level. Skin depot levels were highest for the relatively lipophilic PT. “Pseudo” skin permeability coefficient (K p) data declined with dose level, suggesting skin saturation had occurred. An in-depth comparison with literature data was conducted and risk assessment of first responder exposure was briefly considered.

Site-specific percutaneous absorption of methyl salicylate and VX in domestic swine.

The site specificity of the percutaneous absorption of methyl salicylate (MeS) and the organophosphate nerve agent VX (O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothioate) was examined in anaesthetized domestic swine that were fully instrumented for physiological endpoints. Four different anatomical sites (ear, perineum, inguinal crease and epigastrium) were exposed to the MeS and the serum levels were measured over a 6-h time period. The dose absorbed at the ear region was 11 microg cm(-2) with an initial flux of 0.063 microg cm(-2)min(-1), whereas at the epigastrium region the dose absorbed was 3 microg cm(-2) with an initial flux of 0.025 microg cm(-2)min(-1). For this reason further studies were carried out with VX on the ear and the epigastrium only. In animals treated with agent on the epigastrium, blood cholinesterase (ChE) activity began to drop 90 min after application and continued to decline at a constant rate for the remainder of the experiment to ca. 25% of awake control activity. At this time there were negligible signs of poisoning and the medical prognosis was judged to be good. In contrast, the ChE activity in animals receiving VX on the ear decreased to 25% of awake control values within 45 min and levelled out at 5-6% by 120 min. Clinical signs of VX poisoning paralleled the ChE inhibition, progressing in severity over the duration of the exposure. It was judged that these animals would not survive. The dramatic site dependence of agent absorption leading to vastly different toxicological endpoints demonstrated in this model system has important ramifications for chemical protective suit development, threat assessment, medical countermeasures and contamination control protocols.

Targeting of salicylate to skin and muscle following topical injections in rats

The process of systemic absorption and tissue targeting efficacy of salicylate (SA) following intracutaneous (i.c.), subcutaneous (s.c.) and intramuscular (i.m.) injections of its sodium salt in rats were evaluated by determining the drug concentration at the injection site and surrounding tissues. After i.c. and s.c. injections, SA was absorbed into the systemic circulation from the muscular vessels as well as the cutaneous or subcutaneous vessels beneath the injection site, and the AUC of the drug in the muscle was extremely high. Following i.m. injection, SA was rapidly absorbed into the systemic circulation mostly from the muscular vein. These results suggested that i.c. and s.c. injections have high degrees of targeting efficacy to the muscle, whereas i.m. injection is not appropriate for drug retention in muscle. In contrast, most of the topically applied drug was absorbed from the cutaneous vessels, and little drug migration to the muscle was observed. Thus, the skin pharmacokinetics of SA after i.c. injection was also markedly different from those after topical application on the skin. These results suggested that the i.c. and s.c. injections may be a good means to improve the targeting ability of drugs to the muscle as well as the skin.

Modeling drug absorption from enteric-coated granules.

A system-approach-based method is proposed for modeling drug absorption from enteric-coated granules. This method was exemplified using enteric-coated granules of aspirin given to healthy subjects. Based on the results obtained, it can be concluded that absorption of salicylate from the granules can be sufficiently described using a first-order linear model with an absorption rate constant of salicylate similar to that reported for an aqueous solution of aspirin administered orally to healthy subjects. The method proposed in this study may contribute to the working library of modeling techniques in pharmacokinetics since it allows direct modeling of the drug absorption process and estimates the absorption rate constant of a drug when its behavior in the body is significantly influenced by a gastric emptying process. i.e., when the absorption rate constant of the drug cannot be estimated on the basis of its cumulative absorption-time profile.

Low volume whole bowel irrigation and salicylate absorption: A Comparison with ipecac charcoal: Olsen KM, Ma FH, Ackermann BH, et al. Pharmacotherapy. 1993;13(3):229–232

Low volume whole bowel irrigation and salicylate absorption: A Comparison with ipecac charcoal: Olsen KM, Ma FH, Ackermann BH, et al. Pharmacotherapy. 1993;13(3):229–232

Low-volume whole bowel irrigation and salicylate absorption: a comparison with ipecac: Olsen KM, Ma FH, Ackerman BH. Pharmacotherapy.1993;13:229-32

Low-volume whole bowel irrigation and salicylate absorption: a comparison with ipecac: Olsen KM, Ma FH, Ackerman BH. Pharmacotherapy.1993;13:229-32

The effect of antacid on aspirin pharmacokinetics in healthy Thai volunteers.

The effect of antacid on aspirin pharmacokinetics and bioavailability was determined in 10 healthy adult male and female volunteers, aged 20-45 years old. Each subject received 650 mg of aspirin orally after an overnight fast. The wash out period was 14 days and then all subjects were given 650 mg of aspirin 10 minutes after antacid (aluminium hydroxide and magnesium hydroxide). Plasma aspirin, salicylate and salicyluric acid levels were determined by a specific high performance liquid chromatographic analysis. Individual plasma profiles were analysed using compartmental and non-compartmental methods. The results show that antacid affected the relative bioavailability of aspirin since the mean peak concentration (Cmax) of aspirin was significantly higher when antacid was given. However, the time to reach peak concentration (Tmax) and the area under the plasma concentration-time curve (AUC) showed no significant difference between the two treatments. It was, therefore, not possible to conclude that the non-bioequivalence was caused by a difference in rate or amount of aspirin absorption, or both. No significant difference was observed in Cmax, Tmax, AUC, t1/2, Ka, Kel of salicylate and salicyluric acid. However, the rate of total salicylate absorption was increased since the absorption rate constant (Ka) was higher when antacid was given. This may provide a more rapid effect of the drug.

In Vitro Release and Intestinal Absorption of Physostigmine Salicylate from Submicron Emulsions

The in vitro release of physostigmine salicylate (PS) from a submicron emulsion and an aqueous solution was studied using the dialysis bag method. These formulations were then perfused to various locations along the rat small intestine (proximal, mid, and distal jejunum), and two lengths (10 and 55 cm). The disappearance of PS from the luminal compartment and its appearance in the blood compartment was monitored. In the in vitro drug release from emulsion experiments, a biphasic appearance of PS in the sink solution was observed, suggesting a possible sustained release from the emulsion. However, absorption data from perfusion studies did not correlate with this in vitro observation. No significant difference was found in absorption from emulsion versus solution in the mid jejunum where PS absorption was maximal. The difference between the two liquid formulations was observed only in those intestinal segments where the absorption was relatively low [absorption rate values of 4.6 ± 0.86 and 9.98 ± 2.04 (log%/min) × 10−3 in the proximal and distal parts of the small intestine, respectively, as compared with 14.0 ± 1.2-14.8 ± 1.1 (log%/min) × 10−3 in the mid jejunum]. In the distal part of the rat small intestine, PS was absorbed significantly better from solution than from the submicron emulsion. Cholinesterase activity in blood samples collected after intestinal perfusion with emulsion or solution revealed lower enzyme activity following emulsion administration.

Effect of phonophoresis on serum salicylate levels

The purpose of this investigation was to determine the effect of ultrasound intensity and mode on serum salicylate levels following phonophoresis. Approximately 12-13 g of a salicylate product (Myoflex) was applied to the right anterior forearm of five males and two females. Randomly ordered ultrasound treatment intensities (0.0 W.cm-2; 1.5 W.cm-2, pulsed 50%; and 1.5 W.cm-2, continuous) were applied through the salicylate-containing product for a 5 min duration. A 7.0 ml blood sample was drawn from the left anterior forearm prior to each treatment and again 2 h after treatment. Analysis of variance indicated that none of the topical salicylate treatments produced an increase in serum salicylate levels. These findings suggest that there is no appreciable absorption of salicylate into the bloodstream following topical application of salicylate with or without the use of ultrasound. Since any penetration of salicylate through the skin would result in an increase in serum salicylate levels, the efficacy of phonophoresis to introduce medication into the subdermal tissue is questionable. These findings suggest that a critical review of phonophoresis in general is indicated.