Studies on the mechanism of action of omeprazole |
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| Authors: | D J Keeling C Fallowfield K J Milliner S K Tingley R J Ife A H Underwood |
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| Affiliation: | 1. Department of Pharmacology, Wroclaw Medical University, Wrocław, Poland;2. Department of Pathomorphology, Wroclaw Medical University, Wrocław, Poland;3. Department and Clinic of Endocrinology, Diabetology and Isotope Therapy, Wroclaw Medical University, Wrocław, Poland;1. Clinical Trial Center and Biomedical Research Institute, Chonbuk National University Hospital, Jeonju-si, Republic of Korea;2. CTCBIO Inc, Hwaseong-si, Kyeonggi-do, Republic of Korea;3. Department of Radiation Oncology, Chonbuk National University, Jeonju-si, Republic of Korea;1. Department of Physics, D.G. Vaishnav College, Chennai, India;2. Research and Development Center, St. Peter''s University, Chennai, India;3. Department of Physics, Presidency College, Chennai, India;1. Department of Physiology, Faculty of Medicine, Near East University, Lefkosa, Cyprus;2. Department of Physiology, Faculty of Medicine, Akdeniz University, Antalya, Turkey;1. Division of Surgical Critical Care, Department of Surgery, Maine Medical Center (MMC), Tufts University School of Medicine, Portland, Maine;2. Department of Surgery, Surgical Residency Program, Maine Medical Center, Tufts University School of Medicine, Portland, Maine;3. Department of Epidemiology, Maine Medical Center, Portland, Maine |
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| Abstract: | The effects of omeprazole on preparations of pig gastric (H+ + K+)-ATPase have been studied. Omeprazole was found to inhibit the (H+ + K+)-ATPase activity in a time-dependent manner. Inhibition was more pronounced at pH 6.1 compared with pH 7.4 and decreased as the concentration of (H+ + K+)-ATPase preparation increased. The potency of omeprazole was therefore highly dependent upon the conditions used. When pre- incubated with (H+ + K+)-ATPase preparation (30 micrograms protein/ml) for 30 min at 37 degrees and pH 6.1, omeprazole inhibited the (H+ + K+)-ATPase activity with an IC50 of 3.9 microM. This inhibition was shown to be irreversible in nature. Whilst omeprazole itself was not very potent as an inhibitor of the (H+ + K+)-ATPase activity at pH 7.4 (IC50 = 36 microM), transient acidification of omeprazole resulted in the formation of a compound(s) which produced marked inhibition at this pH (IC50 = 5.2 microM). The effects of omeprazole in the absence of acidification may have resulted from the rate-limiting formation of this compound. Radiolabelled omeprazole was shown to incorporate into the (H+ + K+)-ATPase preparation in a time-dependent and pH-dependent manner. Omeprazole, radiolabelled in three separate positions (the sulphur atom and the two adjacent carbon atoms), incorporated with equivalent time courses suggesting that the incorporation did not involve a fragmentation of the omeprazole molecule. Under conditions shown to produce a 50% inhibition of (H+ + K+)-ATPase activity, [14C] omeprazole had incorporated to a level of 4-5 nmoles/mg protein. Incorporation continued beyond the point required to produce 100% inhibition of (H+ + K+)-ATPase activity and reached 30 nmoles/mg protein after 5 hr. Prior acidification of the omeprazole resulted in a more rapid initial rate of incorporation although the final level of incorporation was lower than for omeprazole. Omeprazole was also shown to interact with the (Na+ + K+)-ATPase from dog kidney. Omeprazole inhibited the (Na+ + K+)-ATPase activity (IC50 = 186 microM). Acid-degraded omeprazole inhibited the (Na+ + K+)-ATPase activity with greater potency (IC50 = 19 microM) and was also shown to incorporate into this enzyme preparation. |
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