SERUM CONCENTRATIONS OF SALICYLIC-ACID FOLLOWING TOPICALLY APPLIED SALICYLATE DERIVATIVES

OBJECTIVE: TO compare the rate and extent of systemic salicylate absor ption following single and multiple applications of two topically appl ied analgesics, one containing methyl salicylate and the other contain ing trolamine salicylate. DESIGN: Two-period, two-treatment, randomize d, crossover, multiple-dose study in healthy men and women volunteers. PARTICIPANTS: Six men and six women volunteers, 21-44 years of age. I NTERVENTIONS: Subjects applied 5 g of an ointment containing 12.5% met hyl salicylate twice daily for 4 days (8 doses) or a cream containing trolamine 10% twice daily for two doses, to a 10-cm(2) area on the thi gh. Treatment order and leg (right or left) were assigned randomly. Su bjects were crossed over to the alternate treatment on the other leg a fter a minimum washout period of 7 days. MAIN OUTCOME MEASURES: The to tal amount of salicylate recovered in the urine during two dosing inte rvals (24 hours) on each study day, relative to the applied dose, was used to calculate the bioavailability of each product. Mean standard p harmacokinetic parameters including area under the curve, maximum conc entration (C-max) time to maximum concentration, and minimum concentra tions at steady-state were determined from serum concentrations, Serum concentrations were fit to three pharmacokinetic models and the suita bility of each model was evaluated. Estimates of absorption rate const ant, 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 a pplication of methyl salicylate and C-max between 2 and 6 mg/L were ob served following the seventh application on day 4. Both tile extent an d rate of absorption changed after the first 24 hours, The absorption rate constant increased significantly from the first to the seventh do se (first dose absorption rate constant: 0.16 h(-1); seventh dose: 0.2 8 h(-1); p < 0.035), Urinary recovery of total salicylate (salicylic a cid and principal metabolites of salicylic acid) during the first 24 h ours 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 me thyl salicylate was significantly greater than the 1.4% recovered afte r application of trolamine (p < 0.05), Furthermore, the fraction of me thyl salicylate recovered in the urine increased significantly from 15 .5% on day 1 to approximately 22% on the second, third, and fourth day s. CONCLUSIONS: A considerable amount of salicylic acid may be absorbe d through the skin after topical application of methyl salicylate prod ucts and this may increase with multiple applications. Caution is warr anted in patients for whom systemic salicylate may be hazardous or pro blematic.