What is the role of hepatocytes in pharmacokinetics?

Role of Hepatocytes in Pharmacokinetics

Hepatocytes are the primary cellular components of the liver responsible for drug metabolism, playing a crucial role in pharmacokinetics through their extensive metabolic enzyme systems, particularly cytochrome P450 enzymes, which determine drug clearance, bioavailability, and potential drug-drug interactions.

Central Role in Drug Metabolism

• Hepatocytes contain the cytochrome P450 (CYP) family of enzymes, which are responsible for phase I metabolism of many drugs, nutrients, endogenous substances, and environmental toxins 1
• CYP3A4, the main CYP enzyme, is responsible for metabolizing more than 50% of all drugs in the market, making hepatocytes critical in determining drug exposure and effects 1
• Primary hepatocytes have become a standard in vitro tool to evaluate hepatic drug metabolism, cytochrome P450 induction, and drug interactions affecting hepatic metabolism 2
• Hepatocytes are the primary site for bioactivation of drugs to form reactive intermediates, which has implications for idiosyncratic adverse drug reactions 1

Metabolic Pathways and Enzyme Systems

• Hepatocytes contain both phase I (oxidation, reduction, hydrolysis) and phase II (conjugation) metabolizing enzymes that transform drugs into more water-soluble compounds for elimination 3
• The intrinsic clearance of drugs in hepatocytes depends on the interplay between uptake transporters and metabolizing enzymes 4
• Drugs with high hepatic extraction ratios are more dependent on hepatic blood flow for clearance rather than intrinsic enzyme activity 1
• Endogenous CYP isoforms expressed in hepatocytes contribute to the metabolism of active drugs, thereby playing a role in altering the half-life and kinetics of administered medications 1

Drug-Drug Interactions

• Hepatocytes are the primary site for metabolism-related drug-drug interactions (DDIs), which occur when one drug influences the metabolism of another drug 1
• Inhibition or induction of hepatic enzymes by drugs can significantly alter the pharmacokinetics of co-administered medications 1
• The clinical consequences of enzyme induction or inhibition depend on the pharmacological and toxic effects of both the parent drug and its metabolites 1
• When the parent compound is more active than its metabolite, inhibition of metabolism increases drug exposure and therapeutic/toxic effects; conversely, if the parent is a pro-drug, inhibition may decrease efficacy 1

Hepatic Clearance and Distribution

• Hepatic clearance is a function of cardiac output, liver blood flow, and the activity of drug metabolizing enzymes and transporters in hepatocytes 1
• Hepatocytes contain both uptake and efflux transporters that work in concert with metabolizing enzymes to determine the fate of drugs and their metabolites 4
• The interplay between enzymes and transporters in hepatocytes determines whether metabolites formed in the liver are excreted into bile or back into systemic circulation 4
• Drugs primarily targeting the liver (such as GalNAc-siRNA) show significant distribution to hepatocytes compared to plasma, affecting their pharmacokinetic profile 1

Factors Affecting Hepatocyte Function

• Age-related changes can reduce hepatic blood flow by 20-30%, affecting drugs with high hepatic extraction ratios 3
• Sex-related differences in hepatocyte function exist, with women presenting increased activity of CYP3A4 and 2D6 but reduced activity of P-glycoprotein (P-gp) transporters 1
• Disease states can influence hepatocyte function and the occurrence of drug interactions that may not be accounted for by in vitro studies 1
• Large differences in genotype and expression level of metabolic enzymes in hepatocytes can lead to complex influences on actual drug disposition 1

In Vitro Models and Clinical Translation

• Primary human hepatocytes provide the closest in vitro model to human liver and can produce a metabolic profile similar to that found in vivo 5
• Three-dimensional cultures of primary human hepatocytes (spheroids) retain functional characteristics of human liver for extended periods, making them valuable for long-term pharmacokinetic studies 6
• Sandwich-cultured hepatocytes maintain metabolic activities and form a canalicular network, allowing simultaneous investigation of uptake transporters, efflux transporters, and drug-metabolizing enzymes 4
• Despite advances in in vitro models, it remains challenging to extrapolate results to routine clinical practice, where patients may have impaired hepatic function or be taking multiple medications 1

Clinical Implications

• Understanding hepatocyte metabolism is crucial for predicting potential drug-drug interactions and adjusting dosages accordingly 1
• Drugs forming reactive metabolites in hepatocytes (such as certain tyrosine kinase inhibitors) may pose higher risks for hepatotoxicity 1
• High daily drug doses (>50 mg) increase the risk of adverse drug reactions due to greater amounts of reactive intermediates generated by hepatocytes 1
• Prodrugs requiring hepatic activation may show delayed onset of action in patients with impaired hepatocyte function 3