A critical feature of any drug is the ability to reach target tissue at levels sufficient to be effective without being toxic. Being able to accurately predict this feature using in vitro systems is a key component of successful non-clinical and preclinical drug development phases. Analyzing pharmacokinetics in vitro involves selecting the right models to predict the metabolism of the drug. For small molecules, metabolism is mainly occurring in liver, and to a lesser extent kidney and intestine. For large molecules and biologics, metabolism is more complex and involves parts of the immune system as well as liver and endothelium.
The right tissue
The right tissue
The right tissue – a case study
Donor variability in metabolism of small molecules
Drug Metabolism by Cyps in Hepatocytes
Graphic showing metabolism characterization in hepatocytesThe family of cytochrome P450 (CYP450) enzymes play an especially large role in determining the kinetics of distribution and clearance of small molecule drugs throughout the body. The CYP450 enzymes have extensive diversity that is driven by both genetic and non-genetics factors. This means that having a full understanding of the impact of CYP450 diversity in metabolism of any small molecule drug is essential for predicting whether a drug will reach the right tissue at the right concentration in individual patients.
Integrated solutions to choose the right tissue
The most common in vitro model for predicting human pharmacokinetics of small molecule drugs dependent on CYP450 enzymes is the primary human hepatocyte. Primary hepatocytes derived from multiple human donors are an essential model for capturing the genetic diversity. Early screening of CYP450 activity towards a drug can also be performed using pooled donor hepatocytes to ensure all the elements of patient population diversity are present. Having a stable supply of a wide variety of primary hepatocytes and pooled donor primary hepatocytes is an essential component of any small molecule drug discovery program.
References
- Review from Zanger and Schwab, Pharmacology & Therapeutics Volume 138, Issue 1, April 2013, Pages 103-141