DDIs and Liver Cirrhosis Factors

Factors Affecting Inhibitory Drug-Drug Interactions (DDIs) in Liver Cirrhosis

• Five factors influence the extent of inhibitory DDIs in cirrhosis.
• Intrahepatic shunting and sinusoidal capillarization in cirrhosis reduce effective liver blood flow.
• This leads to capacity-limited clearance for drugs with a high extraction ratio as liver function declines.
• Reduced extraction ratio (from 0.64 to 0.31) and capacity-limited clearance for lidocaine in decompensated cirrhotics were observed.
• Drugs with a high extraction ratio (flow-dependent) are more sensitive to metabolic inhibitors as liver dysfunction worsens.
• Drugs with a low extraction ratio (capacity-limited) are affected proportionally to enzyme inhibition, as their clearance depends on intrinsic liver metabolic capacity.
• Flow-dependent drugs' clearance relies on liver perfusion and is mostly unaffected by decreased intrinsic clearance from inhibition.

Plasma Protein Binding and DDIs

• Displacement of drugs from plasma protein-binding sites can influence the magnitude of inhibitory DDIs, if the perpetrator also inhibits metabolism.

Effect of Cirrhosis on Drug Clearance Inhibition

• Studies examined cirrhosis' effect on lidocaine (flow-dependent) and theophylline (capacity-limited) clearance inhibition by fluvoxamine.
• Fluvoxamine reduced lidocaine clearance by ~60% in healthy subjects, prolonging its half-life proportionally.
• CYP1A2 was identified as the main CYP responsible for lidocaine metabolism (in vivo demonstration).
• In Child Grade A cirrhosis, fluvoxamine inhibited lidocaine clearance less (40%).
• No significant effect on clearance or half-life was observed in Child Grade C cirrhosis, despite higher fluvoxamine levels.
• This contradicts theoretical predictions, suggesting other factors overriding the conversion from flow-dependent to capacity-limited clearance.

Cirrhosis-Associated Decrease in CYP1A Content

• Decrease in hepatic CYP1A content (up to 80% in hepatocellular cirrhosis) was proposed as a major determinant of reduced clearance inhibition.
• Close correlation between reduced clearance inhibition and decreased lidocaine clearance was observed.
• Significant CYP1A2 content reduction minimizes the effect of its inhibition.

Theophylline Study

• Theophylline (low extraction ratio, CYP1A2 substrate) was used to investigate fluvoxamine's inhibitory effect in cirrhosis.
• Oral theophylline administration (98-100% bioavailability) was used (safety concerns).
• Theophylline's metabolites are excreted directly into the urine, allowing assessment of the effect on metabolite formation clearance.

Explore the factors that affect inhibitory drug-drug interactions (DDIs) in patients with liver cirrhosis. Learn how liver function and blood flow influence drug clearance and the impact of drug extraction ratios on metabolic inhibition. This quiz will enhance your understanding of pharmacokinetics in cirrhotic patients.