Comparison of methods to study enzyme induction in man.

Area of Science:

• Pharmacology and Toxicology
• Biochemical Markers
• Drug Metabolism

Background:

• Drug-metabolizing enzymes are crucial for drug clearance and efficacy.
• Assessing enzyme induction in humans requires reliable in vivo parameters.
• Individual variability in drug metabolism can complicate assessments.

Purpose of the Study:

• To evaluate the suitability of various in vivo parameters for detecting enzyme induction in healthy male volunteers.
• To assess the impact of phenobarbital, a known enzyme inducer, on selected biochemical and pharmacokinetic markers.
• To determine if a combination of parameters offers a more reliable indication of enzyme induction.

Main Methods:

• Administration of phenobarbital to healthy male volunteers.
• Measurement of urinary D-glucaric acid and 6 beta-hydroxycortisol excretion.
• Assay of serum gamma-glutamyltranspeptidase activity.
• Pharmacokinetic analysis of aminopyrine, including total body clearance, elimination constant, and apparent volume of distribution.

Main Results:

• Phenobarbital significantly increased urinary D-glucaric acid excretion (approx. 7-fold) and 6 beta-hydroxycortisol excretion (approx. 150%).
• Serum gamma-glutamyltranspeptidase activity also increased significantly (approx. 150%) post-phenobarbital.
• Aminopyrine total body clearance more than doubled (from 251 to 551 ml/min), attributed to changes in elimination constant and volume of distribution.
• Urinary aminoantipyrine excretion doubled, while acetyl-aminotipyrine elimination remained largely unaffected.

Conclusions:

• A combination of in vivo parameters, particularly urinary D-glucaric acid excretion, reliably indicates drug-metabolizing enzyme induction in humans.
• D-glucaric acid response to induction surpasses the variability observed with other tested parameters.
• Monitoring multiple markers is essential for accurately assessing alterations in the drug-metabolizing enzyme system.