Physiological Pharmacokinetic Models: Incorporating Hepatic Transporter-Mediated Clearance

Drug transporters are pivotal in drug absorption, distribution, and excretion processes. Including them in physiological-based pharmacokinetic models provides a realistic description of drug transport and disposition, which is critical for model accuracy. Understanding influx/efflux and binding mechanisms in membrane transporters helps predict how drugs move through the body and are eliminated.

The liver participates in drug transport, bile movement, and metabolic clearance. It requires compartment concepts to track drug transfers in and out. Human liver microsomes help predict the metabolic clearance of drugs in the body, making the liver essential for understanding overall drug disposition and elimination.

Hepatic transporters such as organic anion transporting polypeptide 1B1 (OATP 1B1) and multidrug resistance-associated protein 2 (MRP2) mediate hepatobiliary excretion of drugs. These transporters control drug uptake into liver cells and subsequent bile excretion, directly influencing how quickly drugs are cleared from the body and their overall pharmacokinetic profile.

Physiological pharmacokinetic models use physiological parameters, subcellular fractions, and drug-related parameters to evaluate drug concentration-time profiles in plasma and peripheral organs. These parameters integrate organ blood flow, tissue composition, and drug-specific properties to predict realistic drug distribution and elimination patterns.

When multiple drug metabolites are involved, physiological models can become complex. A simplified one-compartment model based on the liver as the only organ of drug disappearance and metabolite formation may be used instead. This approach examines concentration-time profiles of the drug and its primary, secondary, and tertiary metabolites for both oral and intravenous administration.

Drug disposition is understood through influx/efflux and binding mechanisms in microstructures including cellular structures, membrane transporters, surface receptors, genomes, and enzymes. These microstructures collectively determine how drugs are absorbed, distributed, metabolized, and excreted throughout the body, enabling accurate predictions of drug behavior.

Advances in molecular biology and pharmacogenomics have revealed that traditional physiological-based pharmacokinetic models are no longer sufficient. Modern models must incorporate detailed transporter and enzyme information to accurately predict drug disposition, especially when liver transport is involved, enabling more precise human drug predictions during development.