In the recently published article on long-term omeprazole treatment [1], the authors attempted to explain the greater than tenfold elevation of plasma gastrin levels in 10 of 91 patients (11%) enrolled in the long-term omeprazole treatment study. We suggest that most, if not all, of these patients could be genetically determined to lack activity of the major enzyme responsible for metabolizing omeprazole, CYP IIC19. After 1 week of oral omeprazole (20 mg/d) given to both rapid and poor metabolizers, poor metabolizers showed a 2.9-fold greater half-life, a 4.8-fold greater maximum plasma concentration, and an 11.7-fold greater plasma area under the curve of omeprazole than did rapid metabolizers [2]. Poor metabolizer frequency varies ethnically, with about 5% of whites [2] and as many as 22% of Asians [3] expressing the poor metabolizer phenotype. Rapid and poor metabolizers of omeprazole can be identified with a mephenytoin-phenotyping technique [4].

Omeprazole-induced hypergastrinemia and decreased vitamin B₁₂ absorption [5] are significant causes of concern for patients receiving long-term omeprazole therapy. Long-term omeprazole therapy would probably put persons with poor metabolism of omeprazole at increased risk for significant vitamin B₁₂ malabsorption, potentially leading to vitamin B₁₂ deficiency.

We propose that poor metabolizers of omeprazole and s-mephenytoin are those at greatest risk for these and other long-term toxicities associated with omeprazole. Because poor metabolizers of omeprazole cannot readily be identified, we recommend that 1) long-term therapy with omeprazole be limited to the few persons with chronic erosive esophagitis and the Zollinger-Ellison syndrome who cannot be treated with other available therapies; 2) all patients receiving long-term omeprazole therapy have annual gastroscopy and B₁₂ measurements; 3) gastrin levels be measured after 3 months of omeprazole therapy; 4) persons with abnormally high gastrin levels or other omeprazole-related toxicities be phenotyped with mephenytoin; and 5) poor metabolizers of mephenytoin receive a markedly reduced dose of omeprazole (for example, 20 mg once or twice weekly).