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Division of Clinical Pharmacology, Departments of Medicine and
Pharmacology, Georgetown University Medical Center
The human clearance of omeprazole and lansoprazole is conducted
primarily by the hepatic cytochrome P450 (CYP) system. Efficacy data
indicate few differences between these two drugs, but they may exhibit
discrete drug interaction profiles. To compare the potency and
specificity of these drugs as inhibitors of CYP isoforms, we performed
in vitro studies with human liver microsomal preparations. Both drugs were potent, competitive inhibitors of CYP2C19, as measured
by the conversion of S-mephenytoin to 4-hydroxymephenytoin (ki = 3.1 ± 2.2 µM for omeprazole,
Ki = 3.2 ± 1.3 µM for lansoprazole). For omeprazole, the highest concentration at which >70% inhibition of
CYP2C19 was observed with no significant inhibitory effect on other
isoforms was at least 20 times greater than Ki.
Both drugs were competitive inhibitors of CYP2C9-catalyzed conversion of tolbutamide to 4-hydroxytolbutamide (Ki = 40.1 ± 14.8 µM for omeprazole, Ki = 52.1 ± 1.4 µM for lansoprazole) and were noncompetitive inhibitors of CYP3A-catalyzed conversion of dextromethorphan to 3-methoxymorphinan (Ki = 84.4 ± 4.0 µM
for omeprazole, Ki = 170.4 ± 7.1 µM for
lansoprazole). Lansoprazole was at least 5 times more potent
(Ki = 44.7 ± 22.0 µM) than omeprazole
(ki = 240.7 ± 102.0 µM) as an inhibitor
of CYP2D6-mediated conversion of dextromethorphan to dextrorphan. No
inhibition of CYP1A2, assessed by measuring the conversion of
phenacetin to acetaminophen, was noted. Our data suggest that whereas
the inhibitory profiles of these two drugs are similar, lansoprazole
may be the more important in vitro inhibitor of CYP2D6.
Since its inhibition is very potent and has a broad "window of
selectivity," omeprazole seems to be a useful, selective inhibitor of
CYP2C19.
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