Prediction of In-Vivo Antimuscarinic Activity (AMA) by In-Vitro Receptor Binding Assessment and PK/PD Modeling For Prototypical Drugs

Purpose: To establish a tool, termed as antimuscarinic activity (AMA), to predict the incidence of antimuscarinic adverse events (AMAEs).Methods: A literature review, focused on drugs having off-target interaction with muscarinic receptors, was performed. Prototypical drugs olanzapine, diphenhydramine, paroxetine were selected for the analysis. Scopolamine and darifenacin were included as positive and negative controls, respectively. Physiochemical properties, pharmacokinetic data, and clinical incidence of AMAEs for the selected drugs were collected from reported literature. Extrapolation of literature data was carried-out to obtain exposure data. To determine the drugs muscarinic affinity (Ki values), experiments were performed using 3H-QNB and membrane suspensions of M1, M2, and M3. Cmax, values were combined with Ki values to generate the relevant AMA. Validation of the AMA biomarker was carried-out against the reported AMAEs incidence. Results: With the exclusion of scopolamine and olanzapine for CNS and peripheral AMAEs, respectively, AMA ranking was related to the drugs AMAEs.

Name thesis:degree_name

Master of Science

Level thesis:degree_level

Thesis

Discipline thesis:degree_discipline

Pharmaceutics

Year dc:date.available

2007

Author dc:creator

• Obied, Taghrid Y.

Contributors dc:contributor

• Dr. Jurgen Venitz

• parasympathetic nervous system
• acetylcholine
• nicotinic receptor
• muscarinic receptor
• scopolamine
• diphenhydramine
• darifenacin
• Medicine and Health Sciences
• Pharmacy and Pharmaceutical Sciences

Statement dc:rights

• © The Author

Identifier

https://scholarscompass.vcu.edu/etd/1348

OAI identifier oai:identifier

oai:scholarscompass.vcu.edu:etd-2347