This study demonstrated that the bioavailability of ASA was approximately 3 times greater (0.17 ± 0.037 versus 0.059 ± 0.013; P
= 0.02) after rectal administration to fasted horses than after IG administration to nonfasted horses, and the peak plasma ASA concentration was approximately 4 times greater (5.05 ± 0.80 μg/mL versus 1.26 ± 0.10 μg/mL; P
= 0.007). The ASA was eliminated rapidly after IV administration. The tl/2
value of 0.53 ± 0.04 h was higher than the tl/2
of 0.11 ± 0.02 h reported by Lees and colleagues (6
) after IV administration of 19 mg/kg of lysine acetylsalicylate to horses. The difference may be due to the different formulations of ASA used in the 2 studies.
In humans, absorption of drugs, including ASA, is usually poorer after rectal administration than after oral administration (3
). In horses, peak serum concentrations of metronidazole are lower when the drug is given rectally than when an equivalent dose is given by the IG or oral route (12
). There may be several reasons for the enhanced absorption and higher bioavailability of ASA after rectal administration in this study. Gastrointestinal absorption of ASA is determined by the rate of dissolution, the luminal pH, and the rate of gastric emptying (17
). The solubility of ASA is limited in the normal acid environment of the equine stomach and proximal small intestine (18
). In the less acidic environment of the rectum (pH 6.0 to 6.5) (18
), ASA solubility is increased, which should result in greater absorption (20
). In human subjects with oral administration, plasma ASA concentrations peaked sooner, at levels approximately 48% higher, when sodium bicarbonate was administered with ASA than when ASA was administered alone (21
Drugs that are administered in the distal rectum in humans may be subject to reduced first-pass hepatic metabolism (22
). The rectum of the horse is approximately 20 to 30 cm long. Venous drainage of the orad half occurs via the caudal mesenteric vessels, which empty into the portal circulation. Venous outflow from the the distal portion of the rectum, however, drains into the caudal vena cava via the internal iliac or pudendal veins, thus bypassing the portal circulation (23
). It is unlikely that a reduction in first-pass hepatic metabolism after rectal administration contributed significantly to the higher plasma concentrations of ASA in this study, because the ASA suspension was deposited approximately 10 cm orad to the rectum (in the terminal small colon). A portion of drug, however, could have spread to and been absorbed from the caudal rectum (22
), avoiding first-pass hepatic metabolism.
The low absorption of ASA after IG administration may be due to the feeding of hay to the horses before and during the IG-administration experiments. The presence of food in the stomach can lead to slower gastric emptying and increased drug binding by organic matter (24
). In humans, ASA absorption is delayed and plasma ASA concentrations are lower when the drug is administered after a meal (24
). Absorption of orally administered phenylbutazone was reduced by approximately 50% in horses fed hay before and after the drug's administration (25
). The absorption of rectally administered drugs can also be lowered by binding of the drug to organic matter in the gastrointestinal tract (16
). The influence of such drug binding was reduced in this study because feces were removed from the rectum before drug administration; this may have contributed to the increased bioavailability of ASA administered rectally compared with that after oral administration. Similarly, fecal material would be decreased in the rectum of horses with gastrointestinal diseases in which food intake is reduced or absent. Although we realize that the study design (the horses being nonfasted for IG administration) created a condition that would lower the absorption of intragastrically administered ASA, the IG administration of ASA to nonfasted horses would likely mimic the clinical situation in which horses are not routinely fasted before oral administration of NSAIDs.
The peak plasma SA concentrations after IG administration were higher than those after rectal administration of ASA. The presence of food in the stomach of the nonfasted horses would delay gastric emptying and may have resulted in increased gastric retention of ASA. ASA is rapidly hydrolyzed to SA within the gastrointestinal tract (26
). Consequently, larger intestinal concentrations of SA would have been available for absorption, resulting in higher plasma concentration.
Oral administration of NSAIDs, including ASA, can result in gastric irritation and ulceration (27
). Damage to the gastric mucosa may result more from the physical interaction of the drug with the mucosa than from the inhibition of local prostaglandin synthesis. In rats, 100 mg of ASA/kg in a single dose caused significant gastric mucosal irritation when administered orally but no gastric damage when administered rectally (28
). Thus, rectal administration of ASA may prevent the gastric mucosal damage that can occur after oral administration. We did not examine the rectal mucosa of our horses after rectal administration of ASA. Long-term rectal administration of ASA, however, has been shown to cause anorectal ulceration and stricture in humans (29
Orally administered ASA significantly inhibits plasma thromboxane production and prolongs bleeding time in horses (6
). Oral administration of ASA is not always feasible in horses with gastrointestinal disease. Currently in the United States, there is no commercially available preparation of ASA that can be given intravenously. Although an IV formulation of SA is available, SA does not inhibit platelets (10
). To our knowledge, plasma or tissue concentrations of ASA necessary to inhibit thromboxane production in horses have not been determined. Baxter (7
) showed that a single IG dose of ASA of 5 to 20 mg/kg administered to fasted horses significantly inhibited thromboxane production for 3 to 5 d, in a dose-dependent manner. Although we compared the bioavailability of ASA after rectal administration to fasted horses with that after IG administration to nonfasted horses, Kopp and associates (9
) demonstrated that 17 mg/kg of ASA given orally once daily to nonfasted horses significantly reduced serum thromboxane B2
concentrations, to barely detectable levels, during the administration period.
We have shown that a single rectal dose of ASA of 20 mg/kg in fasted horses results in higher peak plasma ASA concentrations and greater bioavailability than the same dose given IG to nonfasted horses. Our findings, when combined with those of Kopp and associates (9
), suggest that rectal administration of ASA should result in adequate inhibition of serum thromboxane production when oral administration is contraindicated. Therefore, under these experimental conditions, our hypothesis that the bioavailability of ASA after rectal administration would be comparable or superior to that after oral administration is supported. Additionally, lower doses than those suggested for IG administration may be sufficient.