Impact of gastric acid suppressants on cytochrome P450 3A4 and P-glycoprotein: consequences for FK506 assimilation.
BACKGROUND
Cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (PGP) are important determinants of the oral bioavailability and clearance of tacrolimus. Cimetidine and omeprazole are known modulators of several CYPs in vitro. In the present study, the impact of cimetidine and omeprazole on tacrolimus exposure and on CYP3A4/PGP activity in vivo was examined.


METHODS
In a cohort of 48 renal transplant recipients who switched standard ulcer prophylaxis with 400 mg of cimetidine daily to 20 mg of omeprazole, dose/weight normalized trough levels of tacrolimus during a 5-day interval before and after switch were compared and further studied using multivariate analysis. In a cohort of 6 healthy volunteers, the effect of a 5-day course of ranitidine, cimetidine, and omeprazole on overall CYP, CYP3A4, and PGP activity in vivo was assessed with the (13)C-aminopyrin breath test and the combined per oral and intravenous (14)C-erythromycin breath and urine test.


RESULTS
Dose/weight normalized trough levels of tacrolimus decreased significantly (-15%) after switch from cimetidine to omeprazole. In healthy volunteers, a significant increase of intestinal CYP3A4 activity was observed after omeprazole, whereas no change was noted after cimetidine/ranitidine. Overall CYP activity was significantly decreased after cimetidine and remained unchanged after omeprazole/ranitidine. No effects on PGP or hepatic CYP3A4 were seen.


CONCLUSIONS
Switching treatment with cimetidine to omeprazole in renal transplant recipients is associated with a decrease of dose/weight normalized trough levels of tacrolimus. Studies in healthy volunteers suggest that this may be explained by an increase of intestinal CYP3A4 activity.
Lemahieu
Wim P D
WP
Division of Nephrology and Laboratory of Digestion and Absorption, Department of Medicine, University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium.
Maes
Bart D
BD
Verbeke
Kristin
K
Vanrenterghem
Yves
Y
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis*; D000328:Adult; D000368:Aged; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D002927:Cimetidine / Q000494:pharmacology*; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D005260:Female; D005744:Gastric Acid / Q000378:metabolism*; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009853:Omeprazole / Q000494:pharmacology*; D016559:Tacrolimus / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000897:Anti-Ulcer Agents; D002927:Cimetidine; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009853:Omeprazole; D016559:Tacrolimus