New perspectives in gastric acid suppression: Genetic polymorphisms predict the efficacy of proton pump inhibitors

Proton pump inhibitors are highly effective in the management of acid-pepti c diseases. These drugs potently inhibit acid secretion from gastric pariet al cells by irreversibly inhibiting activity of the H+, K+ ATPase (proton p ump). Early studies of the pharmacokinetics of proton pump inhibitors demon strated considerable variation in drug clearance rates among patients and h ealthy volunteers. This variation was also reflected in a wide range of the efficacy of acid suppression by standard doses of proton pump inhibitors a mong study subjects; those with slower clearance and higher drug concentrat ions experienced superior acid suppression. Proton pump inhibitors are pred ominantly inactivated by the 2C19 isoform of the hepatic cytochrome P450 mi xed function oxidase system. The cytochrome P450 2C19 gene is polymorphic, with three known inactivating mutations. Individuals with one or two mutant cytochrome P450 2C19 alleles metabolize proton pump inhibitors more slowly than those with two wild-type alleles and experience higher drug levels. A n individual's cytochrome P450 2C19 genotype predicts the degree of acid su ppression in response to a standard dose of a proton pump inhibitor. Emergi ng data suggests that the clinical effectiveness of proton pump inhibitors in the treatment of acid-peptic diseases may also be dependent on cytochrom e P450 2C19 genotype. Copyright (C) 2000 S. Karger AG, Basel.