Oxybutynin

• Modeling Mechanism：

  Oxybutynin induces memory decline through the following mechanisms: ① It lacks P-glycoprotein (P-gp) substrate properties and is highly lipid-soluble (log D>3.3) and has high passive permeability, easily crossing the blood-brain barrier (BBB). Its brain/plasma ratio (B:P=6.27) and unbound brain/unbound plasma ratio (Kp,free=3.30) are significantly higher than other anticholinergic drugs; ② It specifically inhibits M₁cholinergic receptors (key receptors involved in learning and memory consolidation) in the central nervous system, blocking acetylcholine-mediated neural signal transmission and damaging the function of memory-related brain regions such as the hippocampus and cerebral cortex, leading to impairment of cognitive functions such as spatial memory and working memory.

• Related Products：

  Oxybutynin (T1049L)

• Modeling Method：

  Experimental Subject：

  Rats, Sprague-Dawley rats, Male, Body weight 250–300 g, Adult, stable cognitive function period

  Dosage and Administration Route：

  ① Core modelling: Oxybutynin, 0.3 mg/kg (clinical dose equivalent), dissolved in physiological saline, subcutaneous injection;
  ② Control treatment:
  - Positive control: Scopolamine 0.3 mg/kg subcutaneous injection (classic memory impairment model drug);
  - Negative control: Tolterodine 0.3 mg/kg subcutaneous injection (anticholinergic drug with low CNS penetration);
  - Blank control: Subcutaneous injection of equal volume saline solution

  Dosing Frequency and Duration Model：

  Once daily for 7 consecutive days

• Validation：

  1. Behavioral Indicators (Core Validation): - Morris Water Maze: The escape latency was significantly prolonged in the oxybutynin group (more than 30% higher than the control group, p<0.01), and the time spent in the target quadrant was shortened (more than 25% lower than the control group, p<0.01), suggesting spatial learning and memory impairment; - Y Maze: The percentage of spontaneous alternation behavior was significantly reduced (more than 20% lower than the control group, p<0.05), suggesting working memory impairment; 2. Molecular Indicators: - Receptor Expression: The expression of M₁ receptor protein in the hippocampus was significantly downregulated (Western blot analysis, more than 35% lower than the control group, p<0.01); - Neurotransmitters: The content of acetylcholine (ACh) in the cerebral cortex was significantly reduced (more than 40% lower than the control group, p<0.01), and the activity of choline acetyltransferase (ChAT) was decreased (more than 30% lower than the control group, p<0.01); 3. Tissue Distribution Validation: - 7 days after drug administration Two days later, the concentration of oxybutynin in the brain reached 141±27 ng/g, and the concentration of CSF was 0.71±0.26 ng/ml, confirming that the drug effectively penetrated the BBB and accumulated in the central nervous system.

*Precautions：

*References：Callegari E,et,al. A comprehensive non-clinical evaluation of the CNS penetration potential of antimuscarinic agents for the treatment of overactive bladder. Br J Clin Pharmacol. 2011 Aug;72(2):235-46.