T. Tateishi, SG Graham, Y. Krivoruk
Oct 1, 1995
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0
Influential Citations
17
Citations
Quality indicators
Journal
British journal of clinical pharmacology
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 [5-7]. 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 described [11]. Briefly, 3 gCi (0.074 gmol) of [N-methyl-14C]erythromycin (DuPont New England Nuclear, Boston, Mass.) were injected intravenously, and at fixed intervals over the subsequent 60 min the subject breathed into a CO2 collecting system to collect exhaled 14Co2. The specific activity of 14C collected was determined by liquid scintillation counting. The results of the erythromycin breath test Ici : c ;rij i itinmi pbt