Drug metabolic stability in early drug discovery to develop potential lead compounds

Knowledge of the metabolic stability of a new drug substance eliminated by biotransformation is essential for envisaging the pharmacokinetic parameters required for deciding drug dosing and frequency. Strategies aimed at modifying lead compounds may improve metabolic stability, thereby reducing the drug dosing frequency. Replacement of selective hydrogens with deuterium can effectively enhance the drug's metabolic stability by increasing the biological half-life. Further, cyclization, change in ring size, and chirality can substantially improve the metabolic stability of drugs. The microsomal t(1/2) approach for measuring drug in vitro intrinsic clearance by automated LC-MS/MS offers sensitive high-throughput screens with reliable data. The obtained in vitro intrinsic clearance from metabolic stability data helps predict the drug's in vivo total clearance using different scaling factors and hepatic clearance models. This review summarizes all the recent approaches and technological advancements in metabolic stability studies for narrowing down the potential lead compounds in drug discovery. Further, we summarized the potential pitfalls and assumptions made during the in vivo intrinsic clearance estimation from in vitro intrinsic clearance.

Automated summary

Understanding the metabolic stability of a drug substance is crucial for determining dosing and frequency. Modifying lead compounds can improve metabolic stability and reduce dosing frequency. Predicting in vivo total clearance can be done through in vitro intrinsic clearance data and hepatic clearance models.