Species similarities and differences in pharmacokinetics

Area of Science:

• Pharmacokinetics
• Drug Discovery and Development
• Comparative Toxicology

Background:

• Accurate extrapolation of animal drug metabolism data to humans is crucial for drug discovery and development.
• Existing pharmacokinetic principles suggest reasonable extrapolation is possible, but significant limitations persist.

Purpose of the Study:

• To review species similarities and differences in absorption, distribution, metabolism, and excretion (ADME) of drugs.
• To address the predictability of animal data for human risk assessment and identify limitations.

Main Methods:

• Discussion of underlying mechanisms for species-specific ADME.
• Illustration with examples of drug extrapolation.
• Brief overview of allometric and physiological modeling for pharmacokinetic data extrapolation.

Main Results:

• Intrinsic drug absorption may be similar across species due to conserved biomembrane properties.
• Species-specific factors like pH-dependent solubility and first-pass metabolism can alter absorption.
• Renal excretion prediction is relatively successful using glomerular filtration rate ratios.
• Hepatic clearance prediction is feasible when limited by hepatic blood flow.
• Biochemical parameters like protein binding and drug metabolism exhibit significant interspecies variability, posing prediction challenges.

Conclusions:

• Predicting all human pharmacokinetic parameters from animal studies remains challenging.
• Reasonably accurate predictions are possible under well-defined conditions.
• Understanding species-specific ADME mechanisms is key to improving extrapolation accuracy.