Permeation enhancers like sodium dodecyl sulfate (SDS) and caprate increase the intestinal permeability of small model peptide compounds, such as enalaprilat (349 Da). However, their effects remain to be investigated for larger low-permeability peptide drugs, such as hexarelin (887 Da). The objective of this single-pass perfusion study in rat was to investigate the effect of SDS at 5 mg/mL and of caprate administered at different luminal concentrations (5, 10, and 20 mg/mL) and pH (6.5 and 7.4). The small intestinal permeability of enalaprilat increased by 8- and 9-fold with SDS at 5 mg/mL and with caprate at 10 and 20 mg/mL but only at pH 7.4, where the free dissolved caprate concentration is higher than at pH 6.5 (5 vs. 2 mg/mL). Neither SDS nor caprate at any of the investigated luminal concentrations enhanced absorption of the larger peptide hexarelin. These results show that caprate requires doses above its saturation concentration (a reservoir suspension) to enhance absorption, most likely because dissolved caprate itself is rapidly absorbed. The absent effect on hexarelin may partly explain why the use of permeation enhancers for enabling oral peptide delivery has largely failed to evolve from in vitro evaluations into approved oral products. It is obvious that more innovative and effective drug delivery strategies are needed for this class of drugs.

When running in vivo experiments, it is imperative to keep arterial blood pressure and acid-base parameters within the normal physiological range. The aim of this investigation was to explore the consequences of anesthesia-induced acidosis on basal and PGE₂-stimulated duodenal bicarbonate secretion. Mice (strain C57bl/6J) were kept anesthetized by a spontaneous inhalation of isoflurane. Mean arterial blood pressure (MAP), arterial acid-base balance, and duodenal mucosal bicarbonate secretion (DMBS) were studied. Two intra-arterial fluid support strategies were used: a standard Ringer solution and an isotonic Na₂CO₃ solution. Duodenal single perfusion was used, and DMBS was assessed by back titration of the effluent. PGE₂ was used to stimulate DMBS. In Ringer solution-infused mice, isoflurane-induced acidosis became worse with time. The blood pH was 7.15–7.21 and the base excess was about −8 mM at the end of experiments. The continuous infusion of Na₂CO₃ solution completely compensated for the acidosis. The blood pH was 7.36–7.37 and base excess was about 1 mM at the end of the experiment. Basal and PGE₂-stimulated DMBS were markedly greater in animals treated with Na₂CO₃ solution than in those treated with Ringer solution. MAP was slightly higher after Na₂CO₃ solution infusion than after Ringer solution infusion. We concluded that isoflurane-induced acidosis markedly depresses basal and PGE₂-stimulated DMBS as well as the responsiveness to PGE₂, effects prevented by a continuous infusion of Na₂CO₃. When performing in vivo experiments in isoflurane-anesthetized mice, it is recommended to supplement with a Na₂CO₃ infusion to maintain a normal acid-base balance.

Chemotherapy-induced intestinal mucositis is a severe side effect contributing to reduced quality of life and premature death in cancer patients. Despite a high incidence, a thorough mechanistic understanding of its pathophysiology and effective supportive therapies are lacking. The main objective of this rat study was to determine how 10 mg/kg doxorubicin, a common chemotherapeutic, affected jejunal function and morphology over time (6, 24, 72, or 168 h). The secondary objective was to determine if the type of dosing administration (intraperitoneal or intravenous) affected the severity of mucositis or plasma exposure of the doxorubicin. Morphology, proliferation and apoptosis, and jejunal permeability of mannitol were examined using histology, immunohistochemistry, and single-pass intestinal perfusion, respectively. Villus height was reduced by 40% after 72 h, preceded at 24 h by a 75% decrease in proliferation and a sixfold increase in apoptosis. Villus height recovered completely after 168 h. Mucosal permeability of mannitol decreased after 6, 24, and 168 h. There were no differences in intestinal injury or plasma exposure after intraperitoneal or intravenous doxorubicin dosing. This study provides an insight into the progression of chemotherapy-induced intestinal mucositis and associated cellular mucosal processes. Knowledge from this in vivo rat model can facilitate development of preventive and supportive therapies for cancer patients.