Permeability early drug metabolism studies

Seventy-five percent of drug candidates do not reach the clinical trial phase mainly due to poor pharmacokinetics in animal studies (1). Since so many compounds fail in late stage testing, the current trend is to study the pharmacokinetics of lead compounds as early as possible. One of the most important elements of pharmacokinetics is lipophilicity, or a compound s affinity for fat. Usually, the more water soluble a compound is, the lower its lipophilicity. Low water solubility (high-lipophilicity) compounds have a limited oral bioavailability but are usually easily metabolized. On the other hand, low-lipophilicity compounds have poor membrane permeability since membranes are partly composed of fat. 

Absorption, distribution, metabolism, excretion, and toxicology (ADMET) properties determine the pharmacokinetic and safety behavior of compounds and thus to a large part, how effective a compound acts as a drug, how the compound has to be dosed, and what safety window has to be considered. Due to the decisive role of ADMET properties in lead optimization and drug development, these parameters are investigated very early by in vitro systems. For example, Caco-2 cell lines are used to estimate permeability of compounds, while liver microsomes are used to study metabolic stability of novel compounds in vitro [1,2]. 

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