PPIs pharmacokinetics

Proton pump inhibitors
ESOMEPRAZOLE/OMEPRAZOLE, LANSOPRAZOLE, PANTOPRAZOLE, RABEPRAZOLE

"Despite claims to the contrary, all proton pump inhibitors have equivalent efficacy at comparable doses"

Goodman and Gilman, 11 ed.

OMEPRAZOLE is a racemic mixture; ESOMEPRAZOLE is exclusively the active S-isomer
- the R-isomer is converted to the active S-isomer by CYP2C19
- differences in activity of this enzyme alter the effectiveness of OMEPRAZOLE in some patients ("poor metabolizers"), giving ESOMEPRAZOLE a therapeutic advantage
  - the proportion of poor metabolizers varies in populations (e.g., only 10% of caucasians but 70% of South Pacific Islanders are poor metabolizers)

PPIs are acid-labile prodrugs that are administered in acid-resistant formulations (either with an enteric coating, or combined with sodium bicarbonate) - the enteric coatings dissolve in the intestinal lumen where the prodrugs are absorbed and circulate throughout the body

the prodrugs preferentially diffuse into acidified compartments (i.e., the parietal cell canaliculi) where they are protonated, concentrated >1000-fold and converted to the active forms which bind IRREVERSIBLY to H⁺/K⁺ ATPase

timing of administration is critical:
- PPIs must be ADMINISTERED in the fasting state, when gastric motility is low
  - bioavailability is decreased approximately 50% by food because larger amplitude movements crush the protective coatings, exposing the prodrugs to the stomach acid (which is in high concentration) and causing them to be inactivated
- PPIs only inhibit active pumps
  - however, in a fasting state, only 10% of pumps are actively secreting acid and susceptible to inhibition à administer PPIs ~ 1 hour before a meal, so that peak serum concentrations coincide with maximal pump activity

short t½, however, at least 18 hours are required for synthesis of new pump molecules à significant acid inhibition lasts approx. 24 hours
→ once daily dosing
- the long duration of effect means that differences in pharmacokinetic profiles among PPIs are functionally insignificant (with the exception of the poor metabolizers)

full acid inhibition is seen only after 3-4 days of daily medication (similarly, takes 3-4 days for acid secretion to return to normal when drug is stopped)
- higher loading dose is used initially, then reduced after symptoms have been controlled

ESOMEPRAZOLE, LANSOPRAZOLE and PANTOPRAZOLE are available IV for treatment of stress-induced ulcers, particularly in the ICU
- must be given as continuous IV or repeated bolus injections when patients are fasting (only 10% of pumps are active and can be blocked by the drug)