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Kinetics of disopyramide in decreased hepatic function
European Journal of Clinical Pharmacology
|January 1, 1986
Summary
Patients with decreased hepatic function (DHF) require a 25% lower intravenous disopyramide dose. This is due to altered drug binding and elimination kinetics in DHF, impacting disopyramide levels and efficacy.
Area of Science:
- Pharmacokinetics and Drug Metabolism
- Hepatology
- Cardiology
Background:
- Disopyramide is an antiarrhythmic drug whose elimination can be affected by liver function.
- Alpha-1-acid glycoprotein (AAG) is a key protein binding disopyramide, and its levels can decrease in liver disease.
- Understanding disopyramide kinetics in patients with decreased hepatic function (DHF) is crucial for safe and effective dosing.
Purpose of the Study:
- To investigate the elimination kinetics of disopyramide in patients with DHF compared to those with ischemic heart disease (IHD).
- To determine the relationship between disopyramide serum concentration, protein binding, and AAG levels.
- To establish evidence-based dosing recommendations for disopyramide in DHF patients.
Main Methods:
- Intravenous administration of disopyramide (bolus followed by infusion) to patients with DHF (n=9) and IHD (n=11).
- Measurement of total and unbound disopyramide serum concentrations.
- Quantification of serum alpha-1-acid glycoprotein (AAG) levels.
- Analysis of pharmacokinetic parameters including clearance, volume of distribution, and half-life.
Main Results:
- A significant positive correlation was observed between unbound and total disopyramide serum concentrations in both groups.
- The percentage of unbound disopyramide was significantly higher in DHF patients (45.5%) compared to IHD patients (19.4%) at equivalent concentrations.
- Serum AAG levels were significantly lower in DHF patients, correlating negatively with the free fraction of disopyramide.
- Unbound disopyramide clearance, volume of distribution, and half-life were significantly reduced in DHF patients, though total elimination clearance did not differ.
Conclusions:
- Decreased hepatic function significantly alters disopyramide protein binding and elimination kinetics, leading to higher unbound concentrations.
- The reduced serum AAG levels in DHF patients contribute to increased free disopyramide fractions.
- A 25% reduction in intravenous disopyramide dosage is recommended for patients with decreased hepatic function to avoid potential toxicity.