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Absorption of Rivastigmine from Different Regions of the Gastrointestinal Tract in Humans

From Clinical Pharmacology, Novartis Pharmaceuticals, East Hanover, New Jersey (Dr. Lee, Dr. Wang, Dr. Sedek) and Clinical Pharmacology & Discovery Medicine, GlaxoSmithKline, King of Prussia, Pennsylvania (Dr. Hossain).

The objective of this study was to evaluate the rate and extent of absorption and metabolism of rivastigmine (Exelon®, ENA 713) after site-specific delivery of the drug in the gastrointestinal (GI) tract using a naso-intestinal intubation technique. Healthy adult subjects (n = 7) received, on four separate occasions, a 3-mg dose of a rivastigmine solution (2 mg/mL) orally and via a naso-intestinal tube to three GI sites (jejunum, ileum, and ascending colon). On each of the 3 treatment days for regional GI dosing, the tube was progressed to each of the three GI sites, which was determined by a radiographical technique prior to dosing. On the fourth day, following tube withdrawal, the subject received a 3-mg oral dose of a rivastigmine solution. Plasma samples were obtained at different multiple time points, and the plasma concentrations of rivastigmine and its metabolite, NAP 226-90, were determined using a gas chromatography/mass spectrometry (GC/MS) method. Rivastigmine was rapidly absorbed following both oral administration and site-specific delivery to different regions of the GI tract (jejunum, ileum, and ascending colon). Compared with oral administration (AUV_0- = 21 ng•h/mL, C_max = 12.8 ng/mL, and t_max = 0.87 h), delivery of the drug directly into the ileum, jejunum, and ascending colon did not change the extent of absorption, but the time to peak concentration appeared to be smaller (mean t_max ranged from 0.4-0.6 h, with no change in C_max). The relative bioavailability of rivastigmine from all three regions of the GI tract was comparable to that following oral administration. The metabolite levels (AUC, C_max) were also similar among the three different regions of the GI tract when compared to the oral dose. It was concluded that rivastigmine is rapidly and equally well absorbed following an oral dose and after specific delivery to different regions of the small intestine and ascending colon. GI metabolism of rivastigmine to its major metabolite, NAP 226-90, occurs to a similar extent in different segments of the GI tract.

Key Words: Absorption • metabolism • rivastigmine • ENA713 • NAP226-90 • naso-intestinal intubation • jejunum • ileum • colon • human

Address for reprints: Lucy Lee, PharmD, Clinical Pharmacology, One Health Plaza, Building 105 2W078F, Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936.

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