Pharmacokinetics and Medicinal Chemistry Reference Resources for Drug Discovery

Reference materials covering pharmacokinetic parameters and medicinal chemistry principles have been compiled to support medicinal chemists in preclinical drug discovery research. Understanding PK (pharmacokinetics) parameters in drug discovery is fundamental for the development of safe and effective drugs.

When interpreting compound pharmacokinetic (PK) data, it's helpful to have reference values to compare experimental data to. A compound with a measured rat clearance value of 0.3 L/hr/kg, for example, is being removed at a slow rate relative to rat liver blood flow (3.3 L/hr/kg), indicating that the compound is not rapidly metabolized or excreted upon passage through the liver. A compound with a suprahepatic rat clearance value of 6.6 L/hr/kg, on the other hand, is apparently being removed faster than blood travels through the liver, suggesting that either the liver is not the only organ contributing to compound removal, or that the compound is unstable in the blood.

The pharmacokinetics reference table includes common cross-species physiological parameters relevant to PK, including animal size, liver blood flow, kidney blood flow, and body volumes. A more recent set of values with higher rodent blood flow values (by 20-33%) was published in 2011 by a PhRMA working group, and a survey confirming these general values across the industry was published in 2022 by the IQ Consortium Human PK Prediction Working Group based on a survey of various industry groups.

The PK Cheat Sheet has recently been upgraded with the inclusion of minipig PK data. As minipigs gain prominence as a viable non-rodent in vivo model, they play a crucial role in predicting PK, efficacy, and toxicology studies that support human dose predictions.

Medicinal chemists use a variety of physicochemical, structural, and kinetic metrics to design drug candidates that balance potency with favorable drug-like properties. The medicinal chemistry principles cheat sheet highlights key concepts such as lipophilic ligand efficiency, ionization state, and valuable reference tables.