Introduction

Acid-related diseases such as gastro-oesophageal reflux disease (GERD), gastric ulcers, and duodenal ulcers are common disorders characterized by a variety of symp-toms, including heartburn, regurgitation, dysphagia, chest pain, epigastric pain, nausea, and vomiting.1, 2 The lifetime prevalence of gastric and duodenal ulcers in the USA is reported to be as high as 10%.2 Heartburn, the principal symptom of GERD, has been estimated to occur in approximately 40% of the population at least once per month.2 At one large health maintenance organization in northern California, the total cost for acid-related diseases for 1 year reached nearly $60 million.3 There are a number of approaches to the medical management of patients with acid-related diseases. Antacids, often used as a self-prescribed over-the-counter remedy, relieve the symptoms of acid-related diseases but are limited by the fact that they do not heal oesophagitis.2, 4 Histamine type 2 (H2)-receptor antagonists block histamine-induced acid secretion by gastric parietal cells, and were the first drugs to effectively reduce acid secretion.2 These agents effectively relieve symptoms of acid-related diseases, and billions of dollars of prescriptions are written worldwide each year.5 However, the H2-receptor antagonists appear to be significantly less effective than the more recently developed proton pump inhibitors. A third class of drugs, prokinetics, stimulate oesophageal peristalsis, increase lower oesophageal sphincter pressure, and improve gastric emptying.6 However, the literature suggests that prokinetics are not superior to H2-receptor antagonists for acid-related diseases.6 Proton pump inhibitors are the newest and most effective class of agents used for the treatment of acid-related diseases.2, 7 These agents, like antacids and H2-receptor antagonists, decrease gastric acidity, but they do so by inhibiting H+,K+-ATPase in parietal cell membranes, the final common pathway for gastric acid secretion.2 It is this mechanism of action that is responsible for the superior efficacy of the proton pump inhibitors in the healing of GERD and peptic ulcers.2, 7 Of course, efficacy is not the sole consideration when prescribing medical therapy for GERD or peptic ulcer. The clinician must also think about a drug’s safety profile, and the potential for interactions with other agents that may affect absorption, metabolism, distribution, and excretion and that may lead to adverse reactions.5, 8, 9 This is particularly important in patients with peptic ulcer disease, because such disease is more common in the elderly than in younger individuals,3 and elderly patients are likely to be taking a number of medications for other chronic conditions.10, 11 This supplement provides an in-depth look at some important aspects of the newest proton pump inhibitor to join the therapeutic armamentarium for GERD and gastric and duodenal ulcers — rabeprazole. Williams and Pounder review the pharmacology of this new sub-stituted benzimidazole. They note that rabeprazole has several potential advantages over other proton pump inhibitors, including more potent inhibition of H+,K+-ATPase and acid secretion than omeprazole and more rapid inhibition of the proton pump compared with omeprazole, lansoprazole, or pantoprazole. Swan, Hoyumpa, and Merritt follow with a review of the pharmacokinetic profile for rabeprazole. The results summarized in this paper indicate that rabeprazole is rapidly absorbed after oral administration and that its effectiveness is not influenced by the coingestion of either food or antacids. Both the maximum plasma concentration and the area under the time vs. plasma concentration curve for rabeprazole are linearly related to dose, and both the time to maximum plasma concentration and the elimination half-life are dose-independent. Rabeprazole does not accumulate with repeated dosing. End-stage renal disease does not significantly alter any of the pharmacokinetic parameters for rabeprazole, so dosage adjustment is not mandated in patients with kidney disease. While there are significant changes in the pharmacokinetic parameters for rabeprazole in the elderly and in patients with mild to moderate hepatic impairment, the data suggest that accumulation is unlikely and that dosage adjustment need be considered only in individuals whose hepatic function is severely impaired. Humphries and Merritt review clinically important drug–drug interactions for all classes of agents used to treat acid-related diseases. The mechanisms underlying most of these interactions involve the effects of increased gastric pH on drug absorption, and interference with metabolism involving cytochrome P450 (CYP) isozymes. They suggest that newer agents in a given class, such as famotidine for H2-receptor antagonists and rabeprazole for proton pump inhibitors, appear less likely to be involved in clinically significant drug–drug interactions than are older drugs, such as cimetidine and omeprazole. Ishizaki and Horai provide further details on the CYP-mediated metabolism of proton pump inhibitors. They note that the principal CYP isozymes involved in proton pump inhibitor metabolism are CYP2C19 and CYP3A4. Minor mutations in the gene for CYP2C19 are relatively common, and proton pump inhibitor metabolism may be slowed and plasma levels raised in many patients, particularly Asians. The metabolism of rabeprazole is less dependent on CYP2C19 than is that of other proton pump inhibitors, and its pharmacokinetic profile may be less affected by these polymorphisms. Taken together, these articles provide important information that should be considered when prescribing rabe-prazole or any other proton pump inhibitor for the treat-ment of acid-related diseases. The reports discussed, and the authors’ observations, combine to present a clear pic-ture of the beneficial effects of proton pump inhibitors, and of rabeprazole in particular, in a wide range of patients.