Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia.
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia.
Eur J Pharm Biopharm. 2024 Oct;203:114434. doi: 10.1016/j.ejpb.2024.114434. Epub 2024 Aug 2.
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 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) of digoxin and sulfasalazine were not significantly different between SOD1 and WT mice for both sexes. However, the AUC of caffeine was significantly lower (female: 0.79-fold, male: 0.76-fold) in SOD1 compared to WT mice, which was associated with lower AUC (female: 0.76-fold, male: 0.80-fold) and AUC (female: 0.81-fold, male: 0.82-fold). The AUC of caffeine was significantly higher (female: 1.5-fold, male: 1.9-fold) in SOD1 compared to WT mice, suggesting reduced gastric emptying in SOD1 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 compared to WT mice. Reduced systemic and brain/spinal cord exposure of caffeine in SOD1 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.
已知在肌萎缩侧索硬化症（ALS）的症状期，即运动神经元疾病（MND）家族神经退行性疾病的一个成员，小肠和肝脏会发生改变。这些改变如何影响药物的口服吸收和药代动力学尚不清楚。在这项研究中，代表不同肠道转运机制的模型药物（咖啡因用于被动扩散，地高辛用于 P 糖蛋白外排，柳氮磺胺吡啶用于乳腺癌耐药蛋白外排）通过口服灌胃给予出生后 114-120 天的雄性和雌性 SOD1 小鼠（家族性 ALS 模型）和野生型（WT）同窝仔鼠。给药后 15、30、60 或 180 分钟时，采集血液、大脑和脊髓样本。此外，评估了 70 kDa 荧光素异硫氰酸酯-葡聚糖（FITC-葡聚糖）的体内胃排空和咖啡因的离体肠通透性。地高辛和柳氮磺胺吡啶的 AUC 在 SOD1 和 WT 小鼠的两性中均无显著差异。然而，与 WT 小鼠相比，SOD1 小鼠中咖啡因的 AUC 显著降低（雌性：0.79 倍，雄性：0.76 倍），这与 AUC（雌性：0.76 倍，雄性：0.80 倍）和 AUC（雌性：0.81 倍，雄性：0.82 倍）降低有关。与 WT 小鼠相比，SOD1 小鼠中咖啡因的 AUC 显著升高（雌性：1.5 倍，雄性：1.9 倍），表明 SOD1 小鼠的胃排空减少。此外，与 WT 小鼠相比，雄性 SOD1 小鼠的 FITC-葡聚糖胃排空（0.66 倍）和咖啡因离体肠通透性（0.52 倍）显著降低。SOD1 小鼠中咖啡因的全身和大脑/脊髓暴露减少可能是由于胃排空和小肠通透性的改变所致。因此，对于 ALS 中的某些药物，可能需要特定的给药要求，以确保它们保持在安全有效的浓度范围内。
