In-vitro ADME metabolic stability profiling
Wednesday, September 16, 2015 — Poster Session I
- KLT Nguyen
- KR Yu
- X Xu
The present study describes the conventional methods to evaluate the metabolic properties of lead compounds in the preclinical drug development process. It is well known that hepatic microsomal cytochrome P450 (CYP) forms have a major role in the metabolism of drugs and other chemicals. For in-vitro metabolic stability assays, the typical test systems are liver microsomes, CYP isozymes, S9, and hepatocytes from human and animal species used for toxicity or efficacy evaluation. Depending on the goal of the study, these test systems will be performed in concert to enable a more thorough analysis of key metabolic characteristics leading to more informed decisions regarding drug candidates. The selected in-house compounds were tested using the high throughput screening microsomal stability assay with the single-time point to obtain the in-vitro metabolic stability parameter (t 1/2) in mouse for each compound. These mouse microsomal t 1/2 results were then compared with those t 1/2 results in rat and human using the middle throughput metabolic stability assays with the multiple-time point design. In addition, we also obtained other in-vitro parameters of these drugs, including intrinsic permeability, kinetic solubility and protein binding, as well as the t 1/2 obtained from suspended or plated hepatocytes. In this study, we discuss the species difference in t 1/2 between human and animals, and t 1/2 values obtained from different in-vitro test systems. We also discuss the novel technologies in human hepatocyte culture systems, such as HepatoPac and Hµrel to study the extreme cases of long t 1/2 compounds.
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