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PubMedDate not supplied

[Pharmacokinetic study of percutaneous absorption of salicylic acid from baths with salicylate methyl ester and salicylic acid].

Percutaneous uptake of methyl salicylate was investigated by use of Leukona-Rheumabad (Dr. Atzinger) in 10 volunteers. Percutaneous uptake of salicylic acid was investigated by use of Contrheuma-Bad (Spitzner) in 15 volunteers. By use of bathing concentration of 0.03 g/l of methyl salicylate, plasma levels of 220-820 ng/ml were found 1 h after beginning, and 46-193 ng/ml after 6 h. 2.3-8.7 mg of salicyluric acid was eliminated on the first day, and 0.47 to 1.48 mg on the second day. By use of bathing concentration of 0.33 g/l of salicylic acid constant plasma levels of 10 +/- 1.27 ng/ml were found in a period of 24 h. The renal elimination of 0.92 +/- 0.14 at first day, 0.72 +/- 0.11 at second day, and 0.50 +/- 0.08 mg salicyluric acid at third day was found. Salicylic acid was eliminated 0.086 +/- 0.009 resp. 0.079 +/- 0.007 resp. 0.043 +/- 0.011 mg by those days. The half-time of elimination in urine after methyl salicylate bathing is (as with injected salicylic acid) between 2.4 to 4 h. Conversely half-time of elimination in urine by salicylic acid bathing is between 30 to 50 h, and is greater with salicylic acid bathing than with other application forms. This is in agreement with earlier examinations and results which point out the deposition of salicylic acid in skin. Any definitive deposition of salicylic acid in skin by methyl salicylate bathing was not found.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

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.

Administration, Topical↗
PubMed1998

Simultaneous quantitative analysis of methyl salicylate, ethyl salicylate and salicylic acid from biological fluids using gas chromatography-mass spectrometry.

A gas chromatographic-mass spectrometric (GC-MS) assay was developed for the quantitative analysis of methyl salicylate (MeS), ethyl salicylate (ES) and salicylic acid (SA) from biological fluids. The method was validated from 100-microl rat liver homogenate preparations (5 mg/ml protein) in 70 mM KH2PO4 (pH 7.4) buffer and from 100 microl rat plasma. The samples were extracted with chloroform, derivatized with BSTFA and quantitated by GC-MS in the SIM mode. The standard curves ranged from 31 ng/ml to 800 or 1250 ng/ml. Relative standard deviations and bias were less than 11% in plasma and homogenate for all compounds except SA which evidenced greater variability. The assay was used in preliminary experiments to characterize the pharmacokinetics of MeS in rats.

Animals↗
PubMed1992

Development of a prodrug of salicylic acid, salicylic acid-L-alanine conjugate, utilizing hydrolysis by rabbit intestinal microorganisms.

The hydrolysis of salicylic acid-L-alanine conjugate (salicyl-L-alanine) following oral, intravenous, intracaecal and rectal administration (60, 10, 5 and 5 mg kg-1, respectively: salicylic acid equivalent) was examined in rabbits. Salicylic acid was detected in the blood 2 h after oral administration of salicyl-L-alanine and reached a maximum concentration at 10 h, whereas salicyl-L-alanine was rapidly eliminated. In contrast, unchanged salicyl-L-alanine only was found following intravenous administration of salicyl-L-alanine, suggesting that presystemic de-conjugation of salicyl-L-alanine was involved. The intestinal mucosal de-conjugation of salicyl-L-alanine was not recognized in the in-situ intestinal sac preparation with complete mesenteric venous blood collection. Immediate and very extensive salicylic acid formation in the caecum was found following intracaecal administration of salicyl-L-alanine. After oral pretreatment of rabbits with kanamycin sulphate, a significant inhibition of salicylic acid formation following intracaecal administration of salicyl-L-alanine was observed, indicating that the intestinal microorganisms were responsible for the biotransformation of salicyl-L-alanine. In-vitro incubation of salicyl-L-alanine with gut contents showed that the major source of its hydrolysis was the hind gut. Consequently, the blood concentration of salicylic acid was prolonged extensively following rectal administration of salicyl-L-alanine, suggesting the usefulness of salicyl-L-alanine as a prodrug of salicylic acid.

Administration, Oral↗
PubMed1992

A novel prodrug of salicylic acid, salicylic acid-glutamic acid conjugate utilizing hydrolysis in rabbit intestinal microorganisms.

The fate of salicylic acid-glutamic acid conjugate (salicyl-glutamic acid) following oral, intravenous, intracecal and rectal administration (60, 10, 5 and 5 mg/kg, respectively: salicylic acid equivalent) was examined in rabbits. Salicylic acid was detected in the blood 2 h after oral administration of salicyl-glutamic acid and it reached the maximum level (69.4 micrograms/ml) at 18 h after the dose. A high blood concentration of salicylic acid (24.8 micrograms/ml) was observed up to 36 h. But only a small amount of salicyl-glutamic acid was detected in the blood (less than 2.5 micrograms/ml, as salicylic acid). In contrast, unchanged salicyl-glutamic acid was found mainly in the blood following intravenous administration of salicyl-glutamic acid, suggesting that presystemic de-conjugation of salicyl-glutamic acid predominantly occurred. The intestinal mucosal de-conjugation of salicyl-glutamic acid was negligible in the in situ intestinal sac preparation with complete mesenteric venous blood collection. Immediate and very extensive salicylic acid formation in the cecum was found following intracecal administration of salicyl-glutamic acid. After oral pretreatment of rabbits with kanamycin sulfate (6 x 400 mg), a significant inhibition of salicylic acid formation following intracecal administration of salicyl-glutamic acid was observed, indicating that the intestinal microorganisms were responsible for the biotransformation of salicyl-glutamic acid. Also, in vitro incubation of salicyl-glutamic acid with gut contents showed that the primary location of hydrolysis was the hind gut.

Animals↗
PubMed1996

Serum concentrations of salicylic acid following topically applied salicylate derivatives.

OBJECTIVE: To compare the rate and extent of systemic salicylate absorption following single and multiple applications of two topically applied analgesics, one containing methyl salicylate and the other containing trolamine salicylate. DESIGN: Two-period, two-treatment, randomized, crossover, multiple-dose study in healthy men and women volunteers. PARTICIPANTS: Six men and six women volunteers, 21-44 years of age. INTERVENTIONS: Subjects applied 5 g of an ointment containing 12.5% methyl salicylate twice daily for 4 days (8 doses) or a cream containing trolamine 10% twice daily for two doses, to a 10-cm2 area on the thigh. Treatment order and leg (right or left) were assigned randomly. Subjects were crossed over to the alternate treatment on the other leg after a minimum washout period of 7 days. MAIN OUTCOME MEASURES: The total amount of salicylate recovered in the urine during two dosing intervals (24 hours) on each study day, relative to the applied dose, was used to calculate the bioavailability of each product. Mean standard pharmacokinetic parameters including area under the curve, maximum concentration (Cmax), time to maximum concentration, and minimum concentrations at steady-state were determined from serum concentrations. Serum concentrations were fit to three pharmacokinetic models and the suitability of each model was evaluated. Estimates of absorption rate constant, clearance, volume, and fraction absorbed on day 1 were estimated by using the best-fitting model. RESULTS: Salicylic acid could not be detected in serum after trolamine application. However, concentrations between 0.31 and 0.91 mg/L were detected within 1 hour of the first application of methyl salicylate and Cmax between 2 and 6 mg/L were observed following the seventh application on day 4. Both the extent and rate of absorption changed after the first 24 hours. The absorption rate constant increased significantly from the first to the seventh dose (first dose absorption rate constant: 0.16 h-1, seventh dose: 0.28 h-1; p < 0.035). Urinary recovery of total salicylate (salicylic acid and principal metabolites of salicylic acid) during the first 24 hours of the methyl salicylate phase averaged 175.2 mg, exceeding the 6.9 mg (p < 0.05) recovered during the trolamine phase. The recovery of salicylate in the urine in the first 24 hours after application of methyl salicylate was significantly greater than the 1.4% recovered after application of trolamine (p < 0.05). Furthermore, the fraction of methyl salicylate recovered in the urine increased significantly from 15.5% on day 1 to approximately 22% on the second, third, and fourth days. CONCLUSIONS: A considerable amount of salicylic acid may be absorbed through the skin after topical application of methyl salicylate products and this may increase with multiple applications. Caution is warranted in patients for whom systemic salicylate may be hazardous or problematic.

Administration, Cutaneous↗
PubMed1992

Effect of oral pretreatment with antibiotics on the hydrolysis of salicylic acid-tyrosine and salicylic acid-methionine prodrugs in rabbit intestinal microorganisms.

We examined the hydrolysis mechanism of salicylic acid-tyrosine (salicyl-tyrosine) and salicylic acid-methionine conjugate (salicyl-methionine) in rabbits by exploring their behavior following intraduodenal and intracecal administration (72 and 36 mumol/kg, respectively: salicylic acid equivalent). A large amount of salicyl-methionine was absorbed following intraduodenal administration of salicyl-methionine, without being metabolized to salicylic acid in the small intestinal mucosa. On the contrary, salicylic acid was detected in the blood following intraduodenal administration of salicyl-tyrosine, suggesting that salicyl-tyrosine was metabolized in the small intestinal mucosa. After oral pretreatment of rabbits with kanamycin sulfate (6 x 400 mg) or tinidazole (6 x 160 mg), the hydrolysis of salicyl-tyrosine and salicyl-methionine following intracecal administration was inhibited significantly, indicating that the intestinal microorganisms were responsible for the biotransformation of these prodrugs. Furthermore, in rabbits orally pretreated with both kanamycin sulfate and tinidazole, a significant inhibition of salicylic acid formation from salicyl-tyrosine and salicyl-methionine following intracecal administration was observed.

Animals↗
PubMed1985

[Anti-platelet actions of salicylates: in vivo, ex vivo and in vitro effects of choline salicylate].

Effects of choline salicylate, sodium salicylate, choline chloride and acetylsalicylic acid on platelet aggregation in vivo, ex vivo and in vitro in mice were studied. These drugs all inhibited adenosine diphosphate (ADP)-induced respiratory depression, which is closely related to platelet aggregation in vivo, with choline salicylate showing the strongest inhibitory effect. Choline salicylate had a tendency to reduce the mortality of animals injected intravenously with endotoxin, but the other drugs had no such effect. The inhibitory effects of these drugs on ADP-induced platelet aggregation ex vivo were in the order of choline salicylate greater than acetylsalicylic acid congruent to sodium salicylate greater than choline chloride congruent to no effect, and plasma concentrations of protein-unbound salicylic acid at 1 hr after oral administration of drugs were in the order of choline salicylate greater than acetylsalicylic acid congruent to sodium salicylate. The in vitro effects of these drugs were in the order of choline salicylate congruent to sodium salicylate greater than choline chloride congruent to acetylsalicylic acid congruent to no effect. Therefore, it was considered that salicylic acid played an important role on the in vivo, ex vivo and in vitro effects of choline salicylate and that choline increased plasma concentrations of salicylic acid and consequently enhanced the in vivo and ex vivo effects of salicylic acid. Furthermore, the ex vivo effects of choline salicylate were found when ADP-induced platelet aggregation was measured with platelet-rich plasma prepared from blood collected with heparin as anti-coagulant, but not when blood was collected with citrate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1992

A novel prodrug of salicylic acid, salicylic acid-glycylglycine conjugate, utilizing the hydrolysis in rabbit intestinal microorganisms.

The hydrolysis of salicylic acid-glycylglycine conjugate (salicyl-glycylglycine) following oral, intravenous, intracaecal and rectal administration (434, 72, 36 and 36 mumol kg-1, respectively: equivalent to salicylic acid) was examined in rabbits to develop a novel prodrug of salicylic acid. Salicylic acid was detected in the blood 2 h after oral administration of salicyl-glycylglycine and it reached a maximum level (55.6 micrograms mL-1) at 15 h, whereas a small amount of salicyl-glycylglycine was found in the blood. In contrast, unchanged salicyl-glycylglycine was found mainly in the blood following its intravenous administration, suggesting the involvement of presystemic deconjugation in the hydrolysis of salicyl-glycylglycine. Immediate and very extensive salicyclic acid formation in the caecum was observed following intracaecal administration of salicyl-glycylglycine, suggesting that the intestinal microorganisms were responsible for the biotransformation of this compound. In-vitro incubation of salicyl-glycylglycine with caecal content showed that salicyl-glycylglycine was hydrolysed efficiently in the caecum. Consequently, the blood concentration of salicylic acid was prolonged extensively following rectal administration of salicyl-glycylglycine, indicating the usefulness of salicyl-glycylglycine as a prodrug of salicylic acid.

Administration, Oral↗
PubMed1992

Unequal hydrolysis of salicylic acid-D-alanine and salicylic acid-L-alanine conjugate in rabbit intestinal microorganisms.

The behavior of salicylic acid-D-alanine conjugate (salicyl-D-alanine) following intravenous, oral and intracecal administration was examined in rabbits, then compared with that of salicylic acid-L-alanine conjugate (salicyl-L-alanine) as reported previously. Following intravenous administration, salicyl-D-alanine eliminated rapidly from the blood, and its blood concentration was almost identical with that of salicyl-L-alanine. In both cases, salicylic acid could not be detected in the blood, indicating that systemic de-conjugation of D-alanine might not occur. Unchanged salicyl-D-alanine was found in the blood mainly following oral and intracecal administration of salicyl-D-alanine. On the other hand, salicylic acid formed extensively following oral and intracecal administration of salicyl-L-alanine, suggesting that the presystemic de-conjugation of D-alanine and L-alanine was unequal. Furthermore, in vitro incubation of salicyl-D-alanine with cecal content, in which the major source of salicyl-L-alanine hydrolysis is found, showed that the hydrolysis of salicyl-D-alanine was negligible in rabbit intestinal microorganisms.

Administration, Oral↗
PubMed1989

Antiinflammatory action of salicylates: aspirin is not a prodrug for salicylate against rat carrageenin pleurisy.

A current hypothesis postulates that the antiinflammatory effect of aspirin (acetylsalicylic acid) is mediated by its metabolite salicylic acid through inhibition of PGE2 synthesis. We tested this hypothesis in rats with carrageenin-induced pleurisy. Aspirin or salicylate, given orally, reduced exudation and cell migration into the pleural cavity, aspirin being more potent than salicylate. The antiinflammatory effect of aspirin cannot be explained only in terms of salicylate formation. Doses of aspirin and salicylate that inhibit inflammation by 50% result in salicylate levels in the exudate of 70 +/- 12 and 323 +/- 17 micrograms/ml, respectively. At a significant antiinflammatory dose (100 mg/kg), salicylate did not reduce the prostaglandin and thromboxane content of the exudate. This indicates that inhibition of cyclooxygenase is not a likely mechanism for the antiinflammatory effect of salicylate. Salicylate only reduced the amount of 6-keto-PGF1 alpha in the exudate at higher doses (200 mg/kg), while aspirin at an equally antiinflammatory dose (50 mg/kg) reduced the content of 6-keto-PGF1 alpha, TXB2, PGD2 but not of PGE2 in the exudate. It therefore seems unlikely that an inhibition of PGE2 synthesis is the common mechanism by which aspirin and salicylate exert their antiinflammatory effects. These results do not supported the hypothesis that aspirin is a prodrug for salicylate but rather indicate that both compounds may exert their antiinflammatory effects partly by different mechanisms.

Animals↗
PubMed2003

Plasma salicylate from methyl salicylate cream compared to oil of wintergreen.

BACKGROUND: Poison Control Centers follow the acetylsalicylic acid (ASA) treatment guideline to manage unintentional ingestions of topical methyl salicylate liniments. For example, one teaspoon of 30% methyl salicylate cream such as Ben Gay provides an "ASA equivalent dose" of 180 mg/kg for a 10 kg child. The ASA treatment guideline advises emesis with syrup of Ipecac and 24 h home followup for this dose. Both the ASA conversion factor to yield the ASA equivalent dose and the treatment guideline assume 100% bioavailability of the salicylate. The nature of this topical dosage product led the investigators to expect less than complete absorption of methyl salicylate. OBJECTIVE: To compare plasma concentrations of salicylate from ingested methyl salicylate cream with plasma concentrations of salicylate from ingested oil of wintergreen. METHODS: Four adult volunteers consented to an open label, four-way crossover design, with randomization to the following treatments: 1 mL Oil of Wintergreen, U.S.P., 6.7 g of Ben Gay 15% and 20 g of Ben Gay 15% and also to hold 5 g of Ben Gay 15% cream in the buccal cavity for 1 minute and then expectorate. Plasma was collected for salicylate determination, and the results analyzed with a noncompartmental pharmacokinetic model. RESULTS: No plasma salicylate was detected after buccal treatment phase. Relative bioavailability for the low-dose treatment was 0.5 compared to oil of wintergreen. CONCLUSION: Plasma salicylate concentrations from methyl salicylate cream are not equal to those achieved after ingestion of oil of wintergreen. Dosage formulation must be considered when predicting toxicity.

Absorption↗
PubMed1991

Symptomatic salicylate ototoxicity: a useful indicator of serum salicylate concentration?

A three phase study was designed to define further the sensitivity and specificity of symptomatic salicylate ototoxicity (primarily tinnitus) for serum salicylate concentrations. In phase one 260 patients with osteoarthritis and 112 with rheumatoid arthritis, none taking salicylates, were interviewed about their ear symptoms. Their responses were not significantly different from those of 134 salicylate treated patients with rheumatoid arthritis previously reported. In the second phase 56 patients who were taking salicylates, and who volunteered the complaint of tinnitus, had serum salicylate concentrations measured while symptomatic, and 30 (54%) had concentrations less than 1.3 mmol/l. Few tolerated an upward salicylate dose adjustment. For phase three, 94 patients were found to have a salicylate concentration above 2.2 mmol/l on one or more occasion, and these subjects were interviewed. Fifty two patients (55%) had no tinnitus, and tinnitus correlated with the blood salicylate concentration in only 28 (30%). Audiological evaluation of most of the symptomatic patients was carried out, and results were abnormal in the majority, even in those patients not reporting tinnitus. Symptomatic salicylate ototoxicity is too nonspecific and too insensitive to be a useful indicator of serum salicylate concentration.

Adult↗
PubMed2001

Salicylic acid in the serum of subjects not taking aspirin. Comparison of salicylic acid concentrations in the serum of vegetarians, non-vegetarians, and patients taking low dose aspirin.

AIMS: To determine serum salicylic acid concentrations in non-vegetarians and vegetarians not taking salicylate drugs, and to compare these concentrations with those found in patients taking aspirin, 75 mg daily. METHODS: Serum samples were obtained from vegetarians (n = 37) and non-vegetarians (n = 39) not taking salicylate drugs. Non-vegetarians and vegetarians were recruited from the community and from a Buddhist monastery, respectively, in Dumfries and Galloway, Scotland. Patients (n = 14) taking aspirin (75 mg daily) were recruited from the Dumfries diabetic clinic. Serum salicylic acid concentrations were determined using a high performance liquid chromatography method with electrochemical detection. RESULTS: Salicylic acid was detected in every serum sample analysed. Higher serum concentrations of salicylic acid were found in vegetarians than non-vegetarians: median concentrations of 0.11 (range, 0.04-2.47) micromol/litre and 0.07 (range, 0.02-0.20) micromol/litre, respectively; the median of the difference was 0.05 micromol/litre (95% confidence interval for difference, 0.03 to 0.08; p < 0.0001). The median serum concentration of salicylic acid in patients taking aspirin (75 mg daily) was 10.03 (range, 0.23-25.40) micromol/litre, which was significantly higher than that found in non-vegetarians and vegetarians. There was overlap in serum salicylic acid concentrations between the vegetarians and patients taking aspirin. CONCLUSIONS: Salicylic acid, a non-steroidal anti-inflammatory drug, is present in fruits and vegetables and is found in higher concentrations in vegetarians than non-vegetarians. This suggests that a diet rich in fruits and vegetables contributes to the presence of salicylic acid in vivo. There is overlap between the serum concentrations of salicylic acid in vegetarians and patients taking aspirin, 75 mg daily. These findings may explain, in part, the health promoting effects of dietary fruits and vegetables.

Adult↗
PubMed2002

New formulation of chemical peeling agent: 30% salicylic acid in polyethylene glycol. Absorption and distribution of 14C-salicylic acid in polyethylene glycol applied topically to skin of hairless mice.

Salicylic acid is used in chemical peeling procedures. However, they have caused many side effects, even salicylism. To achieve a salicylic acid peeling that would be safer for topical use, we recently developed a new formulation consisting of 30% salicylic acid in polyethylene glycol (PEG) vehicle. In an extension of our previous research, we studied the absorption of 30% salicylic acid labeled with 14C in PEG vehicle applied topically to the intact and damaged skin of male hairless mice. An ointment containing 3 mg salicylic acid in 10 mg vehicle was applied to both groups. In animals with intact skin, 1 h after application the plasma concentration of radioactivity was 1665.1 ng eq/ml, significantly lower than the 21437.6 ng eq/ml observed in mice with damaged skin. Microautoradiograms of intact skin showed that the level of radioactivity in the cornified cell layer was similar at 6 h after application. However, in damaged skin, the overall level of radioactivity showed a decrease by 3 h after application. In the carcasses remaining after the treated intact and damaged skin had been removed, 0.09 and 11.38% of the applied radioactivity remained, respectively. These findings confirm that 30% salicylic acid in PEG vehicle is little absorbed through the intact skin of hairless mice, and suggest that salicylism related to absorption through the skin of quantities of topically applied salicylic acid is not likely to occur in humans with intact skin during chemical peeling with this preparation. This new preparation of 30% salicylic acid in PEG vehicle is believed to be safe for application as a chemical peeling agent.

Absorption↗
PubMed1990

Potentiation by salicylate and salicyl alcohol of cadmium toxicity and accumulation in Escherichia coli.

The toxicity of Cd2+ in Escherichia coli K-12 was potentiated by salicylate and several related compounds. The efficiency of plating on Luria broth plates was reduced by more than 10(5)-fold when 10 mM salicylate and 200 microM CdCl2 were present simultaneously but was unaffected when either compound was present by itself. Synergistic effects were found at pH 7.4 with certain other weak acids (acetyl salicylate [aspirin], benzoate, and cinnamate) and with a nonacidic salicylate analog, salicyl alcohol, but not with acetate or p-hydroxy benzoate. Thus, the synergism with Cd2+ is determined by the structure of the compounds and not merely by their acidity. The kinetics of 109Cd2+ uptake by cells grown and assayed in broth indicated the presence of two uptake systems with Kms of 1 and 52 microM Cd2+ and Vmaxs of 0.059 and 1.5 mumol of Cd2+ per min per g of cells, respectively. The kinetics of uptake for cells grown and assayed with 20 mM salicyl alcohol showed 2.5-fold increases in the Vmaxs of both systems but no change in the Kms. Salicylate-grown cells also exhibited increased rates of 109Cd2+ uptake by both systems. Thus, enhanced uptake of Cd2+ may be responsible for the potentiation of Cd2+ toxicity by salicylate and salicyl alcohol.

Acetates↗