7.23 : Physiological Pharmacokinetic Models: Incorporating Hepatic Transporter-Mediated Clearance

Drug transporters are critical in drug absorption, distribution, and excretion processes. They should be included in physiological-based pharmacokinetic (PBPK) models, which help predict human drug disposition. However, predicting this is challenging during drug development, especially when liver transport is involved. However, with a realistic representation of body transport processes, an accurate model may be possible.

A recent model describes pravastatin's hepatobiliary excretion, mediated by transporters like organic anion transporting polypeptide 1B1 (OATP 1B1) and multidrug resistance-associated protein (2 MRP 2). Traditional PBPK models are no longer sufficient due to advances in molecular biology and pharmacogenomics. Drug disposition is better understood using influx/efflux and binding mechanisms in microstructures like cellular structures, membrane transporters, surface receptors, genomes, and enzymes.

The liver plays a crucial role in drug transport and bile movement, requiring compartment concepts to track drug transfers. Human liver microsomes aid in predicting drug metabolic clearance in the body. With pravastatin, the PBPK model evaluates drug concentration-time profiles in plasma and peripheral organs using physiological parameters, subcellular fractions, and drug-related parameters.

However, the model can become complex when multiple drug metabolites are involved, necessitating simplified approaches. For instance, a one-compartment model based on the liver as the only organ of drug disappearance and metabolite formation has been developed. This model considers the formation of primary, secondary, and tertiary metabolites and examines concentration-time profiles of the drug and metabolites for oral and intravenous drug administration.