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Administrative data

Endpoint:
additional toxicological information
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well-reported study on good scientific principles

Data source

Reference
Reference Type:
publication
Title:
Pharmacokinetics of aspirin and salicylate in relation to inhibition of arachidonate cyclooxygenase and antiinflammatory activity
Author:
Higgs GA, Salmon JA, Henderson B, Vane JR
Year:
1987
Bibliographic source:
Proc Natl Acad Sci USA 84:1417-1420

Materials and methods

Type of study / information:
Relative potency of inhibition of arachidonate cyclooxygenase activity between ASA, SA and other NSAIDs
Test guideline
Qualifier:
no guideline required
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): salicylate (Wellcome), also aspirin (Wellcome)

Results and discussion

Any other information on results incl. tables

Following ASA administration, the peak concentration of ASA in plasma was observed at the first (5 min) measurement. ASA was rapidly and almost completely metabolised to SA, resulting in a rapid decline of plasma ASA concentration to 10% of peak at 1 hour and an undetectable level at 6 hours. After 5 minutes, SA concentration in plasma was 20 times ASA concentration, reaching a peak at 30 minutes to 2 hours. At 6 hours, SA concentration was still 20-30 times peak ASA concentration. Following SA administration, peak plasma SA concentration was reached after 5 minutes and had not declined significantly after 6 hours. Serum from rats treated with ASA did not contain any detectable TXB2 at any measurement from 5 minutes to 6 hours. Over the same time period, the concentration of TXB2 in the serum of rats treated with SA was reduced by 40-90%. The effects of ASA and SA were similar in inflammatory exudates, with reductions of both TXB2 and PGE2 by 40-80% at 30 minutes to 6 hours post administration. It was concluded that inactivation of platelet TXB2 via interaction with COX-1 is primarily due to ASA per se in the pre-systemic circulation before deacetylation to SA on first pass through the portal circulation, however SA did show some activity. On the other hand, the anti-inflammatory effect of ASA via interaction with COX-2 resulting in inhibition of PGE2 was considered primarily due to its metabolite SA, as shown by their similar degree of potency in this study.

Applicant's summary and conclusion

Conclusions:
MeS is not likely to deactivate of platelet TXB2 via interaction with COX-1 since this is primarily due to ASA per se. On the other hand, MeS may have an anti-inflammatory effect via interaction with COX-2 resulting in inhibition of PGE2 since this was considered primarily due to SA.
Executive summary:

A pharmacokinetic study of ASA and SA was carried out in rats in order to determine whether inhibition of prostaglandin synthesis viaCOX-1 and/or COX-2 is specific to ASA or whether this property is common to other salicylates (Higgs, 1987). Male Wistar rats were administered a single oral gavage dose of 200 mg/kg ASA (153 mg/kg as SA) or 200 mg/kg salicylate (SA) in aqueous solution. The disposition of ASA and SA was tracked for up to 6 hours in plasma and in inflammatory exudates. Concentration of TXB2 was measured in serum and exudates, whilePGE2was measured in exudates only. Following ASA administration, the peak concentration of ASA in plasma was observed at the first (5 min) measurement. ASA was rapidly and almost completely metabolised to SA, resulting in a rapid decline of plasma ASA concentration to 10% of peak at 1 hour and an undetectable level at 6 hours. After 5 minutes, SA concentration in plasma was 20 times ASA concentration, reaching a peak at 30 minutes to 2 hours. At 6 hours, SA concentration was still 20-30 times peak ASA concentration. Following SA administration, peak plasma SA concentration was reached after 5 minutes and had not declined significantly after 6 hours. Serum from rats treated with ASA did not contain any detectable TXB2 at any measurement from 5 minutes to 6 hours. Over the same time period, the concentration of TXB2in the serum of rats treated with SA was reduced by 40-90%. The effects of ASA and SA were similar in inflammatory exudates, with reductions of both TXB2 and PGE2 by 40-80% at 30 minutes to 6 hours post administration. It was concluded that inactivation of platelet TXB2 via interaction withCOX-1 is primarily due to ASA per se in the pre-systemic circulation before deacetylation to SA on first pass through the portal circulation, however SA did show some activity. On the other hand, the anti-inflammatory effect of ASA via interaction withCOX-2 resulting in inhibition of PGE2 was considered primarily due to its metabolite SA, as shown by their similar degree of potency in this study.