Is diclofenac a valuable CYP2C9 probe in humans?

Area of Science:

• Pharmacology
• Genetics

Background:

• Assessing genetically determined CYP2C9 activity in humans is crucial, with few validated in vivo probes available.
• Diclofenac is an in vitro CYP2C9 substrate with potential as a well-tolerated in vivo probe.
• Previous studies highlight the need for reliable probes to measure CYP2C9 activity.

Purpose of the Study:

• To validate diclofenac as an in vivo probe for CYP2C9 activity by correlating urinary metabolic ratios with metabolic clearance.
• To investigate the relationship between diclofenac's metabolic ratio and its metabolic clearance in healthy volunteers.

Main Methods:

• Eighteen healthy volunteers received a single 50 mg oral dose of enteric-coated diclofenac.
• Pharmacokinetics of diclofenac were monitored over 48 hours, including blood and urine samples.
• CYP2C9 alleles were identified using genomic DNA sequencing.

Main Results:

• Significant inter-individual variability in diclofenac absorption was observed, with absorption delays up to 12 hours.
• No correlation was found between the urinary 4'-hydroxydiclofenac/diclofenac metabolic ratio and metabolic clearance.
• A trend towards lower metabolic clearance in heterozygous CYP2C9 subjects was noted but lacked statistical significance.

Conclusions:

• Enteric-coated diclofenac is not suitable as an in vivo CYP2C9 probe due to variable intestinal absorption.
• Diclofenac may still hold potential as a CYP2C9 probe in alternative formulations, given observed trends in metabolic clearance.
• Further research with different diclofenac formulations is warranted to explore its utility in quantifying CYP2C9 activity.