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The Role of Drug Metabolism and Pharmacokinetics in Lead Discovery and Optimization

The goal of lead optimization within the discovery phase of drug development is a multifaceted process, drawing from various compound properties to hone in on analogs that demonstrate the strongest potential for targeted therapies. Drug metabolism and pharmacokinetic (DMPK) property assessment is crucial to achieving desired biological activities and for determining safety profiles. DMPK data provides the assays necessary for testing new chemical entities (NCEs) in regard to their absorption, distribution, metabolism, and excretion (ADME) properties, to find high quality leads for development.

As most drugs are administered orally, oral bioavailability is a critical area of focus. It is a measure of the fraction of a compound that successfully reaches systemic circulation. Increasing a drug’s absorption and half-life, and minimizing the first-pass effect are important for optimization of an orally administered drug. The half-life determines how long a drug stays in the body; a longer half-life increases oral bioavailability, and can also minimize the dosage and frequency necessary for a drug to be effective. The first-pass effect is a phenomenon of drug metabolism where a significant amount of the drug is lost to the absorption process before reaching systemic circulation.

Another important factor in drug metabolism and lead optimization is the role of cytochrome P450 (CYP) enzymes in the body. CYP enzymes are mostly found in the liver, using oxidizing xenobiotics and making them more water soluble for easy disposal. CYPs are known for their potential impact on drug-drug interactions which should be minimized for safety. Additionally, reactive metabolites generated as products of metabolism, are believed to be involved in the covalent binding of xenobiotics to certain proteins in the liver, which are associated with hepatoxicity.

Drug metabolism and pharmacokinetics form an integral part of lead discovery and optimization, impacting the efficacy and safety of compounds.  There are many established assays and hybrid assays used in lead optimization that are designed for the DMPK environment. Additionally, continuing advances in scientific technologies and methodologies also provide researchers with increasing precision, speed, and complexity important in drug discovery and development.

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Categories: Toxicology and Pharmacology

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