Pharmacokinetic interactions between indomethacin and paracetamol in the rat.

The influence of concurrent administration of paracetamol with indomethacin on the plasma concentrations of these drugs was studied in rats. Orally administered paracetamol reduced the plasma levels of indomethacin during the first 2 hours after oral administration. Later, 16 and 24 hours after administration of indomethacin, the plasma levels exceeded the control values due to the concurrent oral administration of paracetamol. These data suggest that paracetamol delayed the absorption of indomethacin. In contrast the plasma concentrations of paracetamol were not influenced substantially by indomethacin. When paracetamol was co-administered subcutaneously with oral indomethacin, the plasma levels of the latter drug were not influenced. It is concluded that the protective effect of paracetamol against the gastric injuring side effect of indomethacin, which also occurs with subcutaneous administration of paracetamol, cannot be solely due to lowered plasma concentrations of indomethacin.

Butyl hydroxy toluene antagonizes the gastric toxicity but not the pharmacological activity of acetylsalicylic acid in rats.

Butyl hydroxy toluene reduced gastric erosion due to acetylsalicylic acid in the rat, but not the antiinflammatory, anti-pyretic and analgesic activity. By itself, BHT exhibited activity only in the test on analgesia.

Protective effects of prostaglandins against ulcerogenic activity of indomethacin during different stages of erosion development in rat stomach. Role of acid and bicarbonate secretion.

Prostaglandin E2 (PGE2) and PGF2 beta decreased the gastric erosive activity of orally administered indomethacin in a dose-dependent manner, when given as a continuous intravenous infusion in the conscious rat. PGE2 protected both during the initial stage of erosion induction and during the later outgrowth to larger erosions. Moreover PGE2 was able to stop the eroding process at any stage as long as the infusion continued. Both PGs were protective only in doses which also reduced the histamine-stimulated acid secretion. PGE2 protected the stomach against indomethacin-induced erosions even in the presence of exogenously administered acid. An infusion of PGE2 stimulated the secretion of bicarbonate in the stomach during some minutes but had no effect during prolonged infusion. These results suggest that, although effects on secretion of acid and bicarbonate were found, these effects cannot be the (only) explanation for the cytoprotective effects observed. Furthermore the protective effect of PGE2 is not confined to any specific stage of the development of indomethacin-induced gastric injury.

The influence of paracetamol on the anti-inflammatory, the anti-pyretic and the analgesic activity of indomethacin.

Interactions between indomethacin (INDO) and paracetamol (PAR) with regard to their anti-inflammatory, anti-pyretic and analgesic activities were studied in rats. The anti-inflammatory and anti-pyretic effects of INDO and PAR were additive. Although antagonism was observed in the analgesic test, the effect of the combination was not inferior to that of PAR alone.

Protection by paracetamol against various gastric irritants in the rat.

Four nonsteroid anti-inflammatory drugs (NSAID), indomethacin, phenylbutazone, ibuprofen, and glafenine, caused erosions in the rat stomach in a dose-dependent manner. Paracetamol, which has been shown to protect against the gastric erosive activity of aspirin, reduced the gastric toxicity of indomethacin but was ineffective against the erosive activity of phenylbutazone and glafenine. Only the high erosion score of a large dose of ibuprofen was partly decreased by paracetamol. The gastric damaging effects of necrotizing concentrations of ethanol and sodium hydroxide were strongly reduced by paracetamol, but the erosive activity of hydrochloric acid was only slightly decreased by paracetamol. Thus, although paracetamol protected the gastric mucosa against various noxious agents, this drug was not able to protect against every type of gastric damage. Paracetamol might be protective by stimulating the biosynthesis of prostaglandins in the stomach wall.

Indomethacin and paracetamol: interaction with prostaglandin synthesis in the rat stomach.

Using ex vivo incubation of mucosal strips the production of prostaglandins (I2- and E-like PGs) in the rat stomach was demonstrated by bioassay. Indomethacin inhibited this PG synthesis 1 and 4 h after oral drug administration. Paracetamol stimulated the production of PGs when given by itself but could not prevent the inhibitory action of indomethacin. Protection of the stomach by paracetamol against the injuring effect of indomethacin is therefore not due to preservation of the production of protective PGs.

The influence of paracetamol on the erosive activity of indomethacin in the rat stomach.

Indomethacin induced erosions in the glandular part of the rat stomach in a dose-dependent manner. Gastric erosions became apparent about 15 min after administration of indomethacin and the damage was maximal at about 4 h. The erosive activity of indomethacin administered subcutaneously was similar to that after oral administration, confirming the data of other authors. The erosive activity of subcutaneously applied aspirin, however, was far less than that of oral administered aspirin and it was not dose dependent. In a dose-dependent manner, paracetamol reduced the incidence of gastric erosions induced with indomethacin; this effect was independent of the route of administration of either drug. Paracetamol was also effective when given 0.5 or 1 h before indomethacin. Orally administered paracetamol also reduced the incidence of gastric erosions induced with aspirin but after subcutaneous administration, paracetamol had no protective effect. The differences between the erosive activities of indomethacin and aspirin are discussed with emphasis on the differentiating influence of paracetamol on the incidence of gastric erosions. Direct contact with the mucosa is apparently more important for the erosive activity of aspirin than for that of indomethacin. Possible mechanisms by which paracetamol exerts its protective activity are proposed.