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Inter- and intrasubject variation in diazepam free fraction
Clinical Pharmacology and Therapeutics
|August 1, 1979
Summary
Significant intersubject variation exists in diazepam free fraction, influenced more by environmental than genetic factors. This variation impacts drug response and requires further investigation in specific patient populations.
Area of Science:
- Pharmacokinetics
- Drug Metabolism
- Clinical Pharmacology
Background:
- Diazepam free fraction exhibits considerable intersubject variability.
- Understanding factors influencing diazepam binding is crucial for optimizing therapeutic outcomes.
Purpose of the Study:
- To quantify intersubject variation in diazepam free fraction.
- To explore the influence of factors like sex, albumin, age, genetics, and physiological state on diazepam binding.
Main Methods:
- Plasma samples from 74 healthy subjects were analyzed for diazepam free fraction.
- Twin studies (dizygotic vs. monozygotic) were conducted to assess genetic vs. environmental influences.
- Diazepam free fraction was also measured in uremic patients pre- and post-hemodialysis and in fed vs. fasting states.
Main Results:
- Significant intersubject variation in diazepam free fraction was observed (0.97% to 1.99%).
- Female subjects showed a skewed distribution towards higher free fractions compared to males.
- Albumin and age accounted for only a small portion of the variation; environmental factors appeared more dominant than genetic factors.
- Uremic patients exhibited higher prehemodialysis free fractions that decreased post-hemodialysis.
- Postprandial changes in free fraction varied significantly among individuals.
Conclusions:
- Intersubject variability in diazepam free fraction is substantial and influenced by multiple factors.
- Environmental factors play a more significant role than genetic factors in diazepam binding.
- Physiological states like uremia and feeding can alter diazepam free fraction, necessitating individualized dosing considerations.