Intestinal Permeability and Oral Absorption of Selected Drugs Are Reduced in a Mouse Model of Familial Alzheimer's Disease.

Abstract

Compared with the significant number of studies reporting altered abundance and function of drug transporters at the blood-brain barrier (BBB) in Alzheimer's disease (AD), the impact of AD on the abundance of intestinal drug transporters and the subsequent effects on oral drug absorption have received little attention. We have reported the altered abundance of some small intestinal drug transporters in a familial mouse model of AD; however, whether this leads to altered oral drug absorption is unknown. The current study examined plasma concentrations of caffeine and diazepam (markers for transcellular passive transport), digoxin (P-glycoprotein substrate), and valsartan (multidrug resistance-associated protein 2 substrate) following oral administration to 8-10 month old female wild-type (WT) and APPswe/PSEN1dE9 (APP/PS1) transgenic mice, a commonly used mouse model of familial AD. The plasma exposure of valsartan and digoxin was significantly (p < 0.05) lower in APP/PS1 animals compared with WT mice, whereas the plasma concentrations of the passive transcellular markers caffeine and diazepam did not significantly differ between the two genotypes. To assess whether the reduced oral absorption of valsartan and digoxin was due to decreased intestinal transport, the ex vivo transport of the previously mentioned drugs and mannitol (a marker of paracellular transport) across the jejunum of WT and APP/PS1 mice was assessed over 120 min. In line with the in vivo absorption studies, the permeability of caffeine and diazepam did not significantly differ between WT and APP/PS1 mice. The permeability of 3H-digoxin through the APP/PS1 mouse jejunum was lower than that measured through the WT jejunum; the average amount (relative to dose applied) permeating the tissue over 120 min was 0.22 ± 0.11% (mean ± SD) for the APP/PS1 jejunum and 0.85 ± 0.3% for the WT jejunum. A 1.9-fold reduction in the average amount of valsartan permeating the jejunum of APP/PS1 mice relative to that of WT mice was also detected. Although no apparent morphological alterations were observed in the jejunal tissue of APP/PS1 mice, the permeability of 14C-mannitol across the jejunum from APP/PS1 mice was lower than that across the WT jejunum (Papp= 10.7 ± 3.7 × 10-6 and 6.0 ± 3.4 × 10-6 cm/s, respectively), suggesting tightened paracellular junctions in APP/PS1 mice. These studies are the first to demonstrate, in APP/PS1 mice, reduced intestinal permeability and the absorption of drugs commonly prescribed to people with AD for their comorbidities. If these findings translate to people with AD, then modified dosing regimens may be necessary for selected drugs to ensure that their plasma concentrations remain in the effective range.