Omeprazole inhibits nocturnal and meal-stimulated gastric acid secretion and can potentially alter the intra-gastric pH-dependent process of orally administered drugs. We describe a patient in whom omeprazole probably interfered with drug delivery.

A 61-year-old Japanese man with a history of abnormal electrocardiographic records was admitted because of clustered anginal attacks. He had several bouts of duodenal ulcer disease with activation a few days earlier. Omeprazole (20 mg in the morning) was given orally. Coronary angiography showed spontaneous vasospasms reproducing chest pain. Intravenous nitroglycerin successfully controlled his anginal attacks. However, after it was replaced by oral administration of isosorbide dinitrate sustained-release tablets [1] (20 mg twice daily), benidipine hydrochloride [2] (4 mg twice daily), and nicorandil [3] (5 mg three times daily) in combination with omeprazole, asymptomatic myocardial ischemia was observed electrocardiographically during daily activity in the hospital. When omeprazole was replaced by famotidine (20 mg twice daily), myocardial ischemia disappeared both during a treadmill exercise test and during ambulatory electrocardiography, despite the use of the same antianginal therapy.

In some patients, omeprazole can maintain a neutral intragastric pH throughout an entire day [4]. Technical difficulties did not permit us to evaluate plasma isosorbide dinitrate levels in this patient; however, an in vitro study has shown that the dissolution of a sustained-release isosorbide dinitrate tablet under the neutral pH was almost the same as that under the acidic pH [5]. The early phase (30 min) of benidipine dissolution in a pH of 6.5 is 30% slower than that in a pH of 1.0 (Kyowa Hakko Kogyo Co. Ltd., Tokyo, Japan. Unpublished data). No previous data were available from the drug manufacturer (Chugai Pharmaceutical Co. Ltd., Tokyo, Japan) or the literature regarding the pH-dependent dissolution of nicorandil.

In 24-hour gastric pH monitoring on the seventh day of each treatment with famotidine or omeprazole Figure 1, omeprazole achieved a neutral pH nearly throughout the day, even after meals, whereas famotidine produced a substantial increase predominantly at night. Omeprazole lowered the C_max and area under the curve (from 0 to 4 hours) of nicorandil by 20% and 38%, respectively, and it also reduced those of benidipine by 11% and 7%, respectively, compared with famotidine. These diminished drug deliveries could potentially reduce their antianginal effects.

View larger version (29K): [in this window] [in a new window]   Figure 1. 24-hour gastric pH monitoring and pharmacokinetic study during famotidine and omeprazole therapy. Arrows represent mealtimes. AUC = area under the curve; Cmax = maximum serum concentration.

We suggest that clinicians consider the drug delivery system in patients receiving proton pump inhibitor therapy and that the manufacturers re-examine whether drug dissolution can be altered by the "unphysiologic" intragastric pH produced by omeprazole.