Plasma, brain and spinal cord concentrations of caffeine are reduced in the SOD1G93A mouse model of amyotrophic lateral sclerosis following oral administration

Abstract

Modifications to the small intestine and liver are known to occur during the symptomatic disease period of amyotrophic lateral sclerosis (ALS), a member of the motor neuron disease (MND) family of neurodegenerative disorders. How these modifications impact on oral absorption and pharmacokinetics of drugs remains unknown. In this study, model drugs representing different mechanisms of intestinal transport (caffeine for passive diffusion, digoxin for P-glycoprotein efflux, and sulfasalazine for breast cancer resistance protein efflux) were administered via oral gavage to postnatal day 114–120 male and female SOD1^G93A mice (model of familial ALS) and wild-type (WT) littermates. Samples of blood, brain and spinal cord were taken at either 15, 30, 60 or 180 min after administration. In addition, the in vivo gastric emptying of 70 kDa fluorescein isothiocyanate-dextran (FITC-dextran) and the ex vivo intestinal permeability of caffeine were assessed. The area under the plasma concentration–time curves (AUC_plasma) of digoxin and sulfasalazine were not significantly different between SOD1^G93A and WT mice for both sexes. However, the AUC_plasma of caffeine was significantly lower (female: 0.79-fold, male: 0.76-fold) in SOD1^G93A compared to WT mice, which was associated with lower AUC_brain (female: 0.76-fold, male: 0.80-fold) and AUC_{spinal cord} (female: 0.81-fold, male: 0.82-fold). The AUC_stomach of caffeine was significantly higher (female: 1.5-fold, male: 1.9-fold) in SOD1^G93A compared to WT mice, suggesting reduced gastric emptying in SOD1^G93A mice. In addition, there was a significant reduction in gastric emptying of FITC-dextran (0.66-fold) and ex vivo intestinal permeability of caffeine (0.52-fold) in male SOD1^G93A compared to WT mice. Reduced systemic and brain/spinal cord exposure of caffeine in SOD1^G93A mice may therefore result from alterations to gastric emptying and small intestinal permeability. Specific dosing requirements may therefore be required for certain medicines in ALS to ensure that they remain in a safe and effective concentration range.