Mechanisms underlying the anti-inflammatory activity and gastric safety of acemetacin

Abstract

Background and purpose: Acemetacin is regarded as a pro-drug of indomethacin and induces significantly less gastric damage but the reasons for this greater gastric safety of acemetacin are unclear. The anti-inflammatory effects of acemetacin have been attributed, at least in part, to its hepatic biotransformation to indomethacin. The aim of this study was to determine the effects of acemetacin and indomethacin in an in vivo model of acute inflammation and to examine the importance of biotransformation of acemetacin (to indomethacin) to its anti-inflammatory actions.

Experimental approach: The zymosan airpouch model was used in rats. Indomethacin or acemetacin (2.7-83.8 micromol kg(-1)) were administered orally or directly into the pouch. Leukocyte infiltration, prostaglandin (PG) E(2) and leukotriene (LT) B(4) levels in exudates, and whole blood thromboxane (TX) B(2) synthesis were measured.

Key results: Acemetacin was rapidly converted to indomethacin after its administration. Both acemetacin and indomethacin elicited comparable, dose-dependent reductions of leukocyte infiltration and of PGE(2) and TXB(2) synthesis. However, indomethacin induced more gastric damage than acemetacin and elevated LTB(4) production in the airpouch.

Conclusions and implications: The similar effects of acemetacin and indomethacin on leukocyte infiltration and PG synthesis are consistent with rapid biotransformation of acemetacin to indomethacin. Some of this biotransformation may occur extra-hepatically, for instance in inflammatory exudates. Acemetacin probably exerts actions independent of conversion to indomethacin, given the different effects of these two drugs on LTB(4) production. Such differences may contribute to the relative gastric safety of acemetacin compared to indomethacin.

Figure 1

Leukocyte infiltration, PGE₂ and LTB₄ after zymosan injection into the airpouch. Leukocyte infiltration is expressed as a percentage of the maximal effect, which occurred at 6 h after zymosan administration. Five rats per group. LTB₄, leukotriene B₄; PGE₂, prostaglandin E₂.

Figure 2

Percentage of leukocyte infiltration in rat airpouch exudate following a single oral or local administration of indomethacin or acemetacin. Data are expressed as mean±s.e.m. ^*P<0.05 vs vehicle; five rats per group.

Figure 3

Cyclooxygenase-1 activity, assayed as TXB₂ levels, in rat whole blood following a single oral or local (into airpouch) dose of indomethacin or acemetacin. Data are expressed as mean±s.e.m. P<0.05 vs vehicle, as indicated by bar; five rats per group. TXB₂, thromboxane B₂.

Figure 4

Cyclooxygenase-2 activity, assayed as PGE₂ levels, following a single oral or local (into airpouch) dose of indomethacin or acemetacin. Data are expressed as mean±s.e.m. Bar shows P<0.05 vs corresponding indomethacin group; five rats per group. PGE₂, prostaglandin E₂.

Figure 5

LTB₄ levels in rat airpouch exudates following a single oral or local (into airpouch) administration of indomethacin or acemetacin. Data are expressed as mean±s.e.m. ^*P<0.05 vs vehicle; five rats per group. LTB₄, leukotriene B_4.

Figure 6

Plasma acemetacin (top panel) and indomethacin (bottom panel) concentrations following a single oral or subcutaneous dose of acemetacin (83.8 μmol kg⁻¹). Data are expressed as mean±s.e.m. Eight rats per group.

Figure 7

Gastric damage score 3 h after oral administration of indomethacin or acemetacin. Data are expressed as mean±s.e.m. ^*P<0.05 vs corresponding dose of indomethacin; five rats per group.

Figure 8

Inhibition of whole-blood thromboxane B₂ synthesis in vitro by indomethacin and acemetacin. ^*P<0.05 vs the group that did not receive either drug; five rats per group).