Podcast
Questions and Answers
Which of the following factors can affect the extent of inhibitory drug-drug interactions (DDIs) in liver cirrhosis?
Which of the following factors can affect the extent of inhibitory drug-drug interactions (DDIs) in liver cirrhosis?
In cirrhosis, the clearance of drugs with a high extraction ratio becomes more sensitive to the action of metabolic inhibitors as liver dysfunction progresses.
In cirrhosis, the clearance of drugs with a high extraction ratio becomes more sensitive to the action of metabolic inhibitors as liver dysfunction progresses.
True
The hepatic clearance of drugs with a low extraction ratio is reduced in proportion to the degree of enzyme inhibition.
The hepatic clearance of drugs with a low extraction ratio is reduced in proportion to the degree of enzyme inhibition.
True
What is the effect of plasma protein binding on inhibitory DDIs?
What is the effect of plasma protein binding on inhibitory DDIs?
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Which drug was used in the study to assess the influence of cirrhosis on the inhibition of a flow-dependent drug?
Which drug was used in the study to assess the influence of cirrhosis on the inhibition of a flow-dependent drug?
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Fluvoxamine, a reversible CYP1A2 inhibitor, reduced the clearance of intravenously administered lidocaine by 60% in healthy subjects.
Fluvoxamine, a reversible CYP1A2 inhibitor, reduced the clearance of intravenously administered lidocaine by 60% in healthy subjects.
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In patients with Child grade C cirrhosis, fluvoxamine significantly inhibited lidocaine clearance.
In patients with Child grade C cirrhosis, fluvoxamine significantly inhibited lidocaine clearance.
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What is the primary determinant of the reduction of clearance inhibition in cirrhosis?
What is the primary determinant of the reduction of clearance inhibition in cirrhosis?
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Theophylline is a CYP1A2 substrate with a high extraction ratio.
Theophylline is a CYP1A2 substrate with a high extraction ratio.
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Theophylline's metabolites are further biotransformed before excretion.
Theophylline's metabolites are further biotransformed before excretion.
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Study Notes
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.
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Description
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.
