Jejunal and ileal absorption of oxprenolol in man: influence of nutrients and digestive secretions on jejunal absorption and systemic availability.

Abstract

and 2INSERM, H6pital Saint-Lazare, 107, rue du Faubourg Saint-Denis, 75010 Paris, France 1 Study I evaluated the absorption of oxprenolol in the ileum, compared to jejunum, in healthy volunteers by an intestinal perfusion technique. Around 80 mg of drug were delivered as a saline solution directly in the small bowel. 2 Samples taken 30 cm distally to the site of perfusion showed that 63% of perfused oxprenolol was absorbed in the jejunum and 48% in the ileum; the differences were significant. 3 The plasma concentration-time profiles were similar for the two perfusions. The AUC and Cmax values of free and conjugated oxprenolol for the jejunal perfusion were significantly lower than those of ileum. They showed large but consistent intersubject variations in the two treatments. 4 Study II investigated, using the same technique, the influence of nutrients and digestive secretions on jejunal absorption and systemic availability of this drug. A saline (in treatments A and B) or a nutrient (in treatment C) solution containing oxprenolol was perfused into the jejunum below a balloon either inflated (A) or deflated (B and C). 5 The disappearance rate of oxprenolol from the jejunum was unaffected by endogenous secretions. The mean amount of drug absorbed along a 30-cm jejunal segment accounted for 52 (A) and 57% (B) of the total amount perfused. The intestinal absorption rate was markedly increased in the presence of nutrients (mean amount absorbed 96% for C). 6 The change in the rate of disappearance from the intestine had no effect on the systemic availability of oxprenolol (mean AUC values 8740, 8250 and 8020 nmol I-1 h for A, B and C, respectively) or its elimination from plasma. 7 The present findings and those obtained previously by intubation and colonoscopic techniques indicate that oxprenolol is not absorbed in the stomach but is absorbed all along the small and large intestines.

Direct In Vivo Human Intestinal Permeability (Peff) Determined with Different Clinical Perfusion and Intubation Methods

“…In the current PBPK GI absorption models, intestinal P eff is a key variable, but direct human data are scarce, especially for low P eff substances. Furthermore, data on direct P eff in the D‐SI are only available for a few drug compounds . In response to this, surrogate parameters, such as P app from Ussing chamber, cell monolayer, and/or P eff from rat perfusion, are applied after IVIVC .…”

Segmental Intestinal Transporters and Metabolic Enzymes on Intestinal Drug Absorption

“…However, variation in segmental absorption was shown to exist for oxyprenolol (Godbillon et al, 1987), talinolol (Grámatte et al, 1996), amoxicillin (Barr et al, 1994), lefradafiban (Drewe et al, 2000), allopurinol (Patel and Kramer, 1986), thymidine analogs (Park and Mitra, 1992), and benzoate (Cong et al, 2001) in both human and animal studies. Undoubtedly, heterogeneity of absorptive carriers would bring about variations in absorption.…”