Should oral medication dose be adjusted in Alzheimer’s disease?

Abstract Background Little is known about the absorption, distribution, metabolism and excretion (ADME) of both AD and non‐AD medicines currently used in people with AD. If drug disposition processes are altered in AD, individuals with AD may be at a greater risk of additional drug‐induced adverse effects, toxicity, or lack of effectiveness. Senescence Accelerated Mouse (SAMP8) is a naturally‐occurring mouse line that displays many characteristics identified in AD patients, and it is considered as a model of sporadic AD. The current study aims to assess if ADME is affected in SAMP8 mice. Method We utilized a proteomics approach to assess drug transporter and metabolising enzyme expression in the small intestine, liver, and kidney in SAMP8 mice. In addition, plasma concentrations of valsartan, digoxin, quetiapine (three model drugs selected based on proteome data) following oral administration in SAMP8 mice were assessed using LC‐MS. The morphological changes of small intestine, liver and kidney was evaluated using H&E staining. The intestine permeability to these drugs was studied using Ussing chamber. Result Following proteomic analysis, PCA plot indicated a clear separation between SAMP8 and SAMR1 intestine, liver and kidney tissue, with global functional analysis indicated altered drug metabolism in the small intestine and liver of SAMP8 mice. The oral pharmacokinetic study revealed a significant elevation in plasma exposure (i.e. AUC) to valsartan and digoxin but reduction to quetiapine in SAMP8 mice compared to their non‐AD control mice. When interpreted together with H&E staining, ex vivo drug permeation study, and proteome data, the increase AUC to valsartan and digoxin is likely due to increased intestine leakiness. For digoxin, despite P‐glycoprotein expression was significantly increased in the small intestine, it failed to compensate the leaky gut. For quetiapine, the reduction in AUC in SAMP8 was due to increased hepatic metabolism, as increased levels of metabolites of quetiapine was detected in the plasma. Conclusion Consistent with our previous observation in APP/PS1 mice, drug disposition following oral administration was also noted in a mouse model of sporadic AD (SAMP8). Clinical study to evaluate altered ADME in people with AD should be considered to achieve precise medication use in people with AD.