Rectal absorption of nitroglycerin in the rat: Avoidance of first-pass metabolism as a function of rectal length exposure
✍ Scribed by A. Kamiya; H. Ogata; Ho-Leung Fung
- Publisher
- John Wiley and Sons
- Year
- 1982
- Tongue
- English
- Weight
- 511 KB
- Volume
- 71
- Category
- Article
- ISSN
- 0022-3549
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✦ Synopsis
Nitroglycerin administered orally undergoes substantial presystemic elimination. It was shown recently that first-pass hepatic metabolism of high clearance drugs can be substantially avoided uia 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 f S D bioavailability of 26.7 f 7.0% ( n = 6j compared to 1.8 f 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 fSD bioavailability increased to 83.5 f 74.5%
( n = 14). However, the variability in bioavailability was extremely large. When the rectal exposure length was restricted to 2.0cm from the anus (at 1.75-mg/kg dose), nitroglycerin bioavailability was estimated a t 91.2 f 30.4% ( n = 6). The plasma nitroglycerin concentrations (>5 min) obtained after this mode of administration were similar to t,hose achieved after intravenous dosing. The data showed that substantial avoidance of presystemic nitroglycerin metabolism can be achieved uia 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 uia the rat rectal route was feasible with an experimental osmotic minipump. This delivery system also produced nearly complete bioavailability for nitroglycerin in the rat.
Keyphrases Nitroglycerin-rectal absorption, avoidance of first-pass metabolism as a function of rectal length exposure, rats Absorption, rectal--nitroglycerin, avoidance of first-pass metabolism as a function of rectal length exposure, rats 0 First-pass metabolism-avoidance as a function of rectal length exposure, nitroglycerin, rats Nitroglycerin undergoes extensive and variable firstpass metabolism when administered orally in rats (1-3) and in humans (4). Recent studies showed that rectal administration of lidocaine, propranolol, and salicylamide in rats led to substantial avoidance of first-pass metabolism of these drugs (5-7). The possibility of similar improvement in bioavailability of nitroglycerin, another high-clearance drug, through the rectal route has been suggested (5). This hypothesis, however, has not been tested.
T h e studies reported here were designed, therefore, to determine the bioavailability of nitroglycerin after rectal administration in rats. Since drug spreading in the colon and rectum may lead to reduction of avoidance of first-pass metabolism (5), rectal dosing of nitroglycerin was carried out with three different lengths of rectal exposure to examine this effect. Finally, an experimental rectal delivery system was tested to explore whether sustained and complete absorption of nitroglycerin was feasible uia the rectal route.