The effect of ionized species on microsomal binding
Michael H Abraham1, Rupert P Austin
1Department of Chemistry, University College London, 20 Gordon Street, London WC1H OAJ, UK. m.h.abraham@ucl.ac.uk
European Journal of Medicinal Chemistry
|November 19, 2011
Summary
Ionized species significantly impact microsomal binding. Protonated bases bind strongly, while anions bind weakly, revealing new insights into drug-microsome interactions.
Area of Science:
- Pharmacokinetics
- Biophysical Chemistry
- Drug Metabolism
Background:
- Previous studies by Austin and co-workers established the effect of neutral molecules on microsomal binding.
- The influence of ionized species on microsomal binding remained largely unelucidated.
- Microsomal binding is a critical factor in drug disposition and pharmacokinetics.
Purpose of the Study:
- To determine the role and impact of ionized species on microsomal binding.
- To quantitatively assess the binding affinities of neutral molecules, protonated bases (cations), and carboxylate anions to microsomes.
- To elucidate the mechanisms underlying the differential binding of charged species to biological membranes.
Main Methods:
- Analysis of existing microsomal binding data using the Abraham and Acree method.
- Development of a linear free-energy relationship (LFER) incorporating descriptors for neutral molecules, cations, and anions.
- Comparative analysis of microsomal binding with partitioning into a cerasome membrane model.
Main Results:
- A unified LFER was established, encompassing neutral molecules, cations, and anions.
- Carboxylic acid anions exhibited approximately 18-fold lower microsomal binding compared to their neutral counterparts.
- Protonated bases demonstrated binding affinities comparable to their neutral forms.
- Protonated bases showed a 10-20 fold increased binding to microsomes compared to cerasome membranes, suggesting specific interactions.
Conclusions:
- Ionized species play a significant role in determining microsomal binding affinity.
- The reduced binding of anions and strong binding of cations are key factors in drug-microsome interactions.
- The enhanced binding of protonated bases is attributed to interactions with phospholipid phosphate groups, a phenomenon not observed in simpler membrane models.
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