Omeprazole does not affect measured CYP3A4 activity using the erythromycin breath test [letter]

Abstract

Omeprazole is a potent inhibitor of H+-ATPase in the gastric parietal cell [1], and is widely used for the treatment of peptic ulcer disease and reflux oesophagitis [2]. Omeprazole has recently been shown to be metabolized by the cytochrome P450 enzymes 3A4 (CYP3A4) and 2C19 (CYP2C19) [3]. Because of the effects of cimetidine on drug metabolism [4], there has been considerable interest in the effects of omeprazole on drug metabolism. Omeprazole has been shown to inhibit the metabolism of a number of drugs including phenytoin, warfarin, and diazepam [5][6][7]. All of these drugs are substrates of CYP2C19 thus suggesting that inhibition of CYP2C19 is produced by omeprazole. A much larger number of drugs are metabolized by CYP3A4 which is the major cytochrome P450 present in human liver. Thus the effects of omeprazole on CYP3A4 activity has considerable importance. Although no single probe has developed universal acceptance as a measure of CYP3A4 activity in vivo, the erythromycin breath test has been the most widely used in vivo index of CYP3A4 activity and we have previously shown that it is inhibited by the CYP3A4 inhibitor ketoconazole [16]. This test involves the intravenous administration of 14C labelled methylerythromycin and the collection of 14Co2 exhaled in breath [8].The purpose of the present study was to determine whether omeprazole, in addition to being a substrate of CYP3A4 also inhibits its activity as measured by the erythromycin breath test.After obtaining the approval of the Vanderbilt Committee for the Protection of Human Subjects, 12 healthy male volunteers aged 20-30 years were recruited into the study and gave written informed consent. The study was a placebo controlled, singleblind crossover design in two parts, each part of similar design. First each volunteer took one placebo capsule (identical to omeprazole 20 mg) twice daily for 7 days. After an overnight fast, the erythromycin breath test was performed on the morning of day seven and then the subjects crossed over to omeprazole. The tests were separated by at least 1 week. For the period of the study the subjects abstained from drinking alcohol and grapefruit juice. The erythromycin breath test was performed as previously The excretion of 14Co2 in the first hour accounted for 3.6 ± 0.6 (s.d.)% of the administered dose following placebo and was similar (3.6 ± 1.1%) after 20 mg omeprazole twice a day for 7 days ( Figure 1).The effects of omeprazole on drug metabolism have been studied in the past and these studies have demonstrated that omeprazole inhibits the metabolism of substrates of CYP2C19. The focus on CYP2C19 substrates preceded the recognition that omeprazole is metabolized not only by CYP2C19, as thought previously, but also by CYP3A4 [10]. Thus it was important to determine whether omeprazole also inhibited the metabolism of CYP3A4 substrates in vivo. CYP3A4 constitutes the dominant portion of cytochrome P450 in human liver and is responsible for the metabolism of a very large range of drugs and endogenous substrates and for th...

In Vitro and in Vivo Drug Interactions Involving Human Cyp3a

“…Also, this study showed that paclitaxel's metabolism was not affected despite CYP3A activity being inhibited, indicating the ability of the test to identify situations where a drug interaction does not occur. Such data, therefore, strengthen the conclusions that omeprazole did not alter CYP3A activity (219) and that interferon only causes a small degree of inhibition (220).…”

Cytochrome P450 3A4 and P‐glycoprotein Expression in Human Small Intestinal Enterocytes and Hepatocytes: A Comparative Analysis in Paired Tissue Specimens

“…Furthermore, in a large collection of human liver samples, there were no significant differences in CYP3A4 protein, CYP3A4 mRNA, verapamil N ‐dealkylation activity, and pregnane X receptor mRNA between cases in which omeprazole was given (n = 9) and cases that had not been exposed to any drugs (n = 39) 34 . In vivo, omeprazole does not affect hepatic CYP3A4 activity as measured by the erythromycin breath test 48 and, if anything, seems to slightly inhibit CYP3A4 49 , 50 , 51 . In any event, the patient numbers were too small to assess whether omeprazole affected CYP3A4 expression in this study.…”

In Vivo Metabolic Activity of CYP2C19 and CYP3A in Relation to CYP2C19 Genetic Polymorphism in Chronic Liver Disease

“…In addition, there is a concern that omeprazole administered to CLD patients and control subjects might have affected the CYP3A4 activity measured by CL cortisol→6β‐HC . However, Furuta et al 39 reported in their in vitro study performed with human liver microsomes that omeprazole is 50 times weaker as an inhibitor for CYP3A4 than for CYP2C19, and Tateishi et al 40 demonstrated that omeprazole did not affect in vivo erythromycin breath test, an established index of CYP3A activity, in healthy subjects. In this context, we consider that the administration of omeprazole did not interfere with CL cortisol→6β‐HC .…”