Rectal absorption of nitroglycerin in the rat: Avoidance of first‐pass metabolism as a function of rectal length exposure

Nitroglycerin administered orally undergoes substantial presystemic elimination. It was shown recently that first‐pass hepatic metabolism of high clearance drugs can be substantially avoided via rectal administration. In applying this concept to nitroglycerin in rats, it was found that unrestricted rectal instillation of nitroglycerin (at 3.5‐mg/kg dose) gave a mean ±SD bioavailability of 26.7 ± 7.0% (n = 6) compared to 1.8 ± 0.9% (n = 5) from oral dosing. This mode of dosing did not lead to complete avoidance of first‐pass metabolism of nitroglycerin in rats. When the rectal exposure length to nitroglycerin was restricted to 3.5 cm from the anus, the mean ±SD bioavailability increased to 83.5 ± 74.5% (n = 14). However, the variability in bioavailability was extremely large. When the rectal exposure length was restricted to 2.0 cm from the anus (at 1.75‐mg/kg dose), nitroglycerin bioavailability was estimated at 91.2 ± 30.4% (n = 6). The plasma nitroglycerin concentrations (>5 min) obtained after this mode of administration were similar to those achieved after intravenous dosing. The data showed that substantial avoidance of presystemic nitroglycerin metabolism can be achieved via rectal administration. This avoidance can be nearly complete if nitroglycerin is limited in exposure to only the lower rat rectum. It was also demonstrated that sustained (at least 24 hr) nitroglycerin delivery via the rat rectal route was feasible with an experimental osmotic minipump. This delivery system also produced nearly complete bioavailability for nitroglycerin in the rat.