Strategic Use of Preclinical Pharmacokinetic Studies and In Vitro Models in Optimizing ADME Properties of Lead Compounds

Abstract

The discovery of novel therapies for a disease often begins with identifying the cellular and biochemical target whose malfunction is implicated in the initiation or progression of the disease. Because abnormally high or low activity of proteins (receptors, enzymes, or transporters) or of the genes that code for these proteins is the underlying cause of most diseases, therapeutic intervention requires modulation of the target protein or gene activity by chemical agents. Identifying the chemical agents that can modulate activities of specific proteins or genes with a high degree of selectivity and potency through rational design or high throughput screening with combinatorial libraries has become a less daunting task in the past two decades. This is because most proteins can be readily expressed, isolated, and structurally characterized, their functional activity can be assessed using in vitro systems, and vast numbers of compounds can be synthesized using combinatorial approaches as potential modulators of their expression or functional activity. However, it is important to recognize that the therapeutic efficacy of these agents in humans can only by achieved if sufficiently high concentration of these compounds can be attained and maintained at the target site. This requires that the compound has appropriate physicochemical properties so that (i) it can be absorbed effectively from the site of administration (e.g. gastrointestinal tract for orally administered compounds), (ii) it escapes extensive metabolism in the liver and other extrahepatic tissues, (iii) it is distributed sufficiently in the target tissue, and (iv) it is not excreted too rapidly via the renal or the hepatobiliary clearance mechanisms.