title: Relative efficacies of gastric proton-pump inhibitors on a milligram basis: desired and undesired SH reactions. Impact of chirality.
abstract: Gastric proton-pump inhibitors (PPIs) are prodrugs. Their acid activation at pH 1.0 inside the canaliculus of a parietal cell should be fast relative to their serum elimination rate. Actually, all PPIs display chemical activation half-lives at pH 1.0 of a few minutes at the most, while being eliminated from serum with a half-life of about 1 h. This is the main reason they show similar antisecretory efficacies on a milligram basis. It is in line with about 5% to 15% higher healing rates in GERD, DU and GU when 40 mg is compared to 20 mg of either omeprazole or pantoprazole. The comparably large biological variation between patient samples explains why some studies show statistically significant differences between the two doses, while others do not. However, it would matter to the individual patient if s/he was the one additionally healed by a 40 mg dose within a defined treatment period. Chemical activation of PPI prodrugs is unwanted in weakly acidic tissue compartments such as lysosomes or secretory granules. However, the ratio of the serum elimination half-life (availability at the target) to the chemical activation half-life at a critical pH 5.0 is reversed only with pantoprazole. when compared to pH 1.0 (i.e. the ratio is < 1 at pH 5.0 and > 1.0 at pH 1.0). This is the basis of the high pH selectivity of pantoprazole. In contrast, rabeprazole is activated at pH 5.0 almost as quickly as it is at pH 1.0 and much faster than it is eliminated from serum. This unwanted reactivity of rabeprazole at pH 5.0 does not contribute to the antisecretory action at pH 1.0 and results in poor pH selectivity. Omeprazole and lansoprazole lie in between, as they are activated, at pH 5.0, about as quickly as they are eliminated from serum. The above activation rates refer to room temperature. At 37 degrees C. the activation rates of all PPIs further increase, by about the same factor of between 3 and 4. This renders their differential pH selectivities even more critical for drug safety. Biological consequences have been reported in the literature. It has been claimed that a dose of 40 mg of the S-enantiomer of omeprazole (esomeprazole) results in 10%-15% higher healing rates in GERD patients, compared to 20 mg omeprazole racemate. The same difference is found when the two doses of omeprazole racemate are compared to each other. This is not surprising, as the chiral PPI prodrug is converted by acid into an achiral cyclic sulfenamide which only then reacts with the proton pump. There is therefore no pharmacodynamic argument in favour of any single enantiomer formulation of any PPI. Moreover, potential pharmacokinetic differences between the enantiomers seem to be of little if any importance in the patient.
authors.affiliation: Dept. of Pharmacology, Byk Gulden, Konstanz, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Kromer
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D001562:Benzimidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D064098:Esomeprazole; D006207:Half-Life; D006801:Humans; D006863:Hydrogen-Ion Concentration; D064747:Lansoprazole; D009853:Omeprazole / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000077402:Pantoprazole; D010295:Parietal Cells, Gastric / Q000187:drug effects*; D011355:Prodrugs; D054328:Proton Pump Inhibitors; D064750:Rabeprazole; D013454:Sulfoxides / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D011355:Prodrugs; D054328:Proton Pump Inhibitors; D013454:Sulfoxides; D064747:Lansoprazole; D064750:Rabeprazole; D000077402:Pantoprazole; D009853:Omeprazole; D064098:Esomeprazole