Absorption of isosorbide-5-mononitrate at specific sites in the gastrointestinal tract.

As part of a development program for controlled- and extended-release formulations of isosorbide-5-mononitrate (ISMN), the rate and extent of drug absorption was evaluated after site-specific delivery in the gastrointestinal (GI) tract. Seven healthy male subjects received, on separate occasions, 20 mg of ISMN solution orally and via nasogastric tube to the jejunum, terminal ileum, and ascending colon. Compared with oral administration (AUC 2,963 hr x ng/mL, Cmax 442 ng/mL, Tmax 0.81 hr), placement of drug directly into the jejunum did not change the extent (AUC 2,844 hr x ng/mL) but increased the rate of absorption (Cmax 630 ng/mL, Tmax 0.28 hr) due to direct placement of drug into the intestine. Administration to the terminal ileum resulted in a rate of absorption comparable to that from the jejunum (Tmax 0.28 hr) but a reduction in extent (mean AUC 2,377 hr x ng/mL). Delivery to the ascending colon resulted in a further decrease in the extent (AUC 2,017 hr x ng/mL) and a "slowing" of the rate of absorption compared with the two intestinal sites (Cmax 392 ng/mL, Tmax 0.68 hr). Overall, bioavailability throughout the GI tract was sufficient to support development of controlled- and extended-release formulations.