Captopril methylation in human liver and kidney: interindividual variability

Area of Science:

• Pharmacology and Toxicology
• Human Metabolism and Drug Elimination

Background:

• Captopril is primarily eliminated via metabolism, with an oral bioavailability of 65%.
• Methylation represents a key metabolic pathway for captopril.
• Understanding metabolic variability is crucial for modulating intracellular drug concentrations.

Purpose of the Study:

• To investigate the methylation of captopril in human liver and renal cortex microsomes.
• To analyze sex-based differences in captopril methylation rates.
• To identify potential subgroups within kidney methylation rates.

Main Methods:

• Analysis of captopril methylation in microsomal fractions from 87 human liver and 70 human renal cortex specimens.
• Quantification of methylation rates in pmol/min/mg.
• Statistical analysis to determine significant differences and subgroup prevalence.

Main Results:

• Captopril methylation rates exhibited an order of magnitude variation in both liver and kidney.
• Human liver methylation rates were significantly higher in women (199 +/- 97 pmol/min/mg) compared to men (126 +/- 88 pmol/min/mg; p < 0.001).
• Human kidney methylation showed no sex difference, with a mean rate of 47 +/- 23 pmol/min/mg, and revealed two distinct subgroups (84% at 42.5 +/- 13.9 and 16% at 90.3 +/- 12.0 pmol/min/mg; p < 0.05).

Conclusions:

• Significant inter-individual and sex-based variability exists in captopril methylation.
• The observed methylation subgroupings in the kidney may influence captopril pharmacokinetics.
• Variability in captopril methylation contributes to the modulation of intracellular drug concentrations.