Specific and dose-dependent enzyme induction by omeprazole in human beings

Area of Science:

• Pharmacology
• Drug Metabolism
• Enzyme Kinetics

Background:

• Omeprazole is known to induce hepatic cytochrome P-450 1A2.
• Previous studies showed induction in poor metabolizers but not extensive metabolizers of S-mephenytoin at 40 mg/day omeprazole.
• The specificity and dose-dependence of omeprazole's inducing potential require further investigation.

Purpose of the Study:

• To investigate the specificity of omeprazole's enzyme-inducing potential.
• To evaluate the dose-dependence of cytochrome P-450 1A2 induction by omeprazole.
• To compare omeprazole's induction profile with phenobarbital-type induction.

Main Methods:

• Utilized the 13C-[N3-methyl]caffeine breath test and plasma caffeine clearance to monitor cytochrome P-450 1A2 activity.
• Administered omeprazole at 40 mg/day and 120 mg/day to extensive metabolizers of S-mephenytoin.
• Measured gamma-glutamyltransferase, urinary D-glucaric acid, and 6 beta-hydroxycortisol levels.

Main Results:

• Cytochrome P-450 1A2 activity increased dose-dependently with omeprazole: 8.5% at 40 mg and 27.2% at 120 mg (p = 0.002).
• Caffeine clearance significantly increased by 31.6% (p < 0.001) at the higher omeprazole dose.
• No significant changes were observed in gamma-glutamyltransferase, D-glucaric acid, or 6 beta-hydroxycortisol levels.

Conclusions:

• Omeprazole exhibits a dose-dependent induction of cytochrome P-450 1A2 activity.
• The induction effect of omeprazole appears specific to cytochrome P-450 1A enzymes.
• Omeprazole's induction profile differs from phenobarbital-type induction, suggesting a targeted effect on specific CYP enzymes.