Pharmacokinetics, activation and mechanism of action of PPIs

John Horn PharmD: Proton pump inhibitors are generally given orally to patients. They have pretty good bioavailability. In some of them, the bioavailability may range from 50 to 70%. However, that's usually taken into account when the dose size is established during the drug development process. Drugs that have lower bioavailability will usually have a higher dose given to produce an effective response in the patient. Therefore, bioavailability by itself isn't a very important distinguishing feature.

One of the things we are concerned about with drugs that are taken orally is whether other things might affect the bioavailability. For example, food. If a patient eats a meal and forgets to take his or her proton pump inhibitor before their meal but takes it during their meal, instead, then there could be a reduction in the absorption of the proton pump inhibitor because of the presence of food in the stomach. That could reduce the response. So some of the proton pump inhibitors - lansoprazole is probably the best example - are markedly affected by food, that is, their absorption is reduced.

Other proton pump inhibitors - like rabeprazole, for example - are not affected by food. If a patient forgets to take it before a meal but while they're having dinner or breakfast, they'll still get good absorption, and the bioavailability will still be good.

Proton pump inhibitors are all prodrugs. That is, the drug that's taken by the patient really isn't active: the drug has to be converted into an active moiety once it gets absorbed into the body. That conversion process occurs in the canalicular space which surrounds the parietal cell.

The plasma half-life is an hour for these drugs. If you gave the active drug and it had an hour half-life in the plasma, you might have to give a higher dose to get enough binding in the parietal cells. But once these drugs bind to the parietal cell, then that parietal cell is done. It's essentially finished for the count and it's not going to come back any time soon.

Thus, the duration of action of the drug is much, much longer than their half-life, probably 36 hours for most of these drugs. By giving the prodrug, you get conversion at the site of action. That has a number of advantages, one of which is that you get very high concentrations of the drug right at the site of action. If you were to give the active drug orally, you'd get high concentrations of the drug all over the body and you might induce a lot more side effects.

Two things determine how fast and when the PPI activates. The first one is a physical chemical property of the PPI, and that's its pKa, which is simply the pH at which half of the drug molecules protonate.

The second thing that determines the activation is the pH in which the drug molecule is sitting. If we think about the parietal cell and the secretory canalicular space and put a PPI into that space, the pKas of the PPIs range from about 3 with pantoprazole to 4 or so for omeprazole, esomeprazole and lansoprazole and with rabeprazole having a pKa of about 5. These are all weak bases, which means that they protonate when you put them in an acid.

If we put these molecules into a very acidic place, like the canalicular space during acid secretion, all of the drugs protonate very quickly. Now the problem is that the canalicular space doesn't stay acidic; it's not like the stomach, which stays acidic all the time, essentially. Canaliculus pH changes with the secretion of hydrogen ion. So while the secretion is actively going on from the parietal cell, canalicular pH is very low. And all the proton pump inhibitors activate very quickly.

But as soon as you stop eating and stimulating the parietal cell, the canalicular pH starts to rise. As it rises up through the pKa of the proton pump inhibitor, that proton pump inhibitor stops activating or slows down vastly. One can see that by looking at activation times of the proton pump inhibitors at different pHs. At a pH of 1, all the drugs activate in a matter of minutes, no difference. Bring the pH up to 3 or 4 or 5 and then you start to see prolongation of the activation times of the proton pump inhibitors that have the lowest pKa.

So the differences in the pKa of the proton pump inhibitors will change the pH range over which they activate and therefore how much drug activates in how fast a period of time.

We know that there are differences in the activation rates of the proton pump inhibitors. The key question, of course, is: Does that make a difference to the patient and how could you employ those differences to better serve, better treat your patients?

There's probably several different ways you can look at that. First of all, a drug that has a more rapid onset is going to be more useful in getting symptoms under control more quickly, because it's going to control pH more quickly. The proton pump inhibitors that have higher pKas are likely to have a more rapid onset, and I think we see that in the data with rabeprazole.

This more rapid onset of pH control, then, can produce a more rapid symptom response. Now a lot of times people think, "Well, why should I be too concerned about rapid symptom control, when I've got a chronic disease like GERD?" Well, GERD is a chronic disease, but we've learned, I think, that it can be treated intermittently. So if one is going to intermittently administer a proton pump inhibitor to a patient with GERD, then every time that patient starts therapy again, it's day one; it's the first dose. Therefore we want a fast onset to get a good response with that first dose.

All of these drugs have very similar molecular weight, so the way you can compare potencies of these agents is just to look at the dose that's given and look at the response. What we find is-and it's pretty obvious just from looking at the doses-that rabeprazole, with a 20 mg dose, is pretty potent. Other agents, for example pantoprazole, where the starting dose is 40 mg, is not as potent as some of the other drugs, particularly rabeprazole and probably even omeprazole. We compensate for that, of course, by just giving more of the drug.

There is a general consensus that as you increase the dose of proton pump inhibitors, you do increase the risk of side-effects. One example of that would be with lansoprazole, where at 30-mg doses, there's probably no difference in side-effect profile than any of the other drugs. But when you go to 60 mg, you start to see more diarrhea, for example, with lansoprazole. That's a fairly common finding with that drug; it does get slightly better action at the higher dose, but you also then incur more side effects.

John Horn PharmD