Evaluation of Omeprazole and Lansoprazole as Inhibitors of Cytochrome P450 Isoforms

• Published in: Drug metabolism and disposition Vol. 25; no. 7; pp. 853 - 862
• Main Authors: KO, J.-W, SUKHOVA, N, THACKER, D, CHEN, P, FLOCKHART, D. A
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.07.1997
• Subjects: 2-Pyridinylmethylsulfinylbenzimidazoles; Biological and medical sciences; Chlorzoxazone - metabolism; Cytochrome P-450 Enzyme Inhibitors; Dextromethorphan - metabolism; Digestive system; Enzyme Inhibitors - pharmacology; Humans; In Vitro Techniques; Isoenzymes - antagonists & inhibitors; Lansoprazole; Medical sciences; Mephenytoin - metabolism; Microsomes, Liver - enzymology; Omeprazole - analogs & derivatives; Omeprazole - pharmacology; Pharmacology. Drug treatments; Phenacetin - metabolism; Tolbutamide - metabolism; Isozyme; Liver; H; Antiulcer agent; K; Microsome; Mechanism; Specificity; Antisecretory agent; Drug interaction; Unspecific monooxygenase; Enzyme; Digestive system; Cytochrome P450; Enzyme inhibitor; Metabolism; In vitro; Omeprazole; Benzimidazole derivatives; Hydrolases; Drug-metabolizing enzyme; exchanging ATPase; Oxidoreductases; Kinetics; Comparative study; Lansoprazole
• ISSN: 0090-9556; 1521-009X

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 ( k i = 3.1 ± 2.2 μM for omeprazole, K i = 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 K i . Both drugs were competitive inhibitors of CYP2C9-catalyzed conversion of tolbutamide to 4-hydroxytolbutamide ( K i = 40.1 ± 14.8 μM for omeprazole, K i = 52.1 ± 1.4 μM for lansoprazole) and were noncompetitive inhibitors of CYP3A-catalyzed conversion of dextromethorphan to 3-methoxymorphinan ( K i = 84.4 ± 4.0 μM for omeprazole, K i = 170.4 ± 7.1 μM for lansoprazole). Lansoprazole was at least 5 times more potent ( K i = 44.7 ± 22.0 μM) than omeprazole ( k i = 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.