PPI metabolism, drug-drug interactions

John Horn PharmD: PPIs are metabolized in the liver, predominantly. And there are some differences between the PPIs and how they're metabolized.

Let me just first say that all of them have some metabolism via the cytochrome P450 system, which is comprised of 10 or 12 different enzymes. The enzyme that's responsible for the metabolism of most of the proton pump inhibitors is called CYP2C19. This enzyme is responsible for the majority of the metabolism of omeprazole, pantoprazole and esomeprazole and about half of the metabolism of lansoprazole. Perhaps 15 or 20% of rabeprazole is metabolized by this enzyme. The majority of rabeprazole metabolism in the liver is via a noncytochrome P450 pathway, another enzymatic pathway, but not in the cytochrome P450 system. And that is actually unique to rabeprazole; none of the other proton pump inhibitors follow that particular pathway for metabolism.

There has been some suggestion in the literature that the thioether metabolite of rabeprazole - this metabolite that comes from the noncytochrome P450 metabolism - may have some activity against H. pylori, just as the parent compound does. But at this point in time, I think it's too early to know whether that is a clinically beneficial activity or if it's just something that it's kind of a bonus that we have it and it probably doesn't make much difference.

Any time a drug is metabolized, there's the potential for it to interact with other drugs, either that are metabolized by the same pathway or if the drug perhaps affects the activity of the enzyme and therefore can affect the metabolism of other drugs.

From what we know about the proton pump inhibitors, it appears that only omeprazole and esomeprazole affect the metabolism of other drugs. And they do that because those two proton pump inhibitors are unique in that they actually interfere with the activity of that 2C19 enzyme that is responsible for their own metabolism. So one can say that they actually inhibit their own metabolism: it's called auto-inhibition. But it also means that they can affect the metabolism of other drugs that are metabolized by the 2C19 pathway.

If you put a patient on omeprazole and you measure the plasma concentrations of omeprazole, what you find is that, over about a five-day period, there's a gradual increase. By day five, the plasma concentration of omeprazole is roughly two times higher than it was on day one after the first dose. This is just evidence of the autoinhibition of the 2C19 activity and accumulation of omeprazole over that time-frame.

A very similar thing happens with esomeprazole, where you get accumulation of the drug over time. It usually takes four or five days to reach a steady state after you start a patient on a particular dose of the drug. There are a few other drugs that are metabolized by the 2C19 pathway. It's interesting that there aren't really very many that go down that pathway. Of the ones that do, there aren't very many that are widely used.

Perhaps the most commonly used drugs that follow that pathway are Valium (diazepam), Dilantin, which is phenytoin, and Warfarin or Coumadin. And all three of those drugs have at least some or a majority of their metabolism down the 2C19 pathway. All of those drugs have been studied with omeprazole to see if they interact. What we find is that Valium, which is predominantly a 2C19 substrate, has a doubling or tripling of its blood levels when it's given with omeprazole. Now that's not usually a big problem for patients, because Valium's a pretty safe drug. But it could be a problem if a patient, for example, got behind the wheel of their car and got into an accident, because they would be driving impaired.

With phenytoin and Warfarin, there are other pathways of metabolism, so that if you block the 2C19 pathway, the drug can trickle out of the body via other pathways. And so we don't usually see a clinically important change. Now, some patients will get a clinically important increase in their phenytoin or Warfarin activity. But fortunately, because these drugs have other pathways, it doesn't cause very many problems.

Because the proton pump inhibitors can so effectively increase pH in the stomach, one has to be concerned that that might affect the absorption of other drugs. That effect can be both positive and negative. For example, some drugs, like antibiotics, tend to be acid-labile; if you put them into the acid of the stomach, they break down and then they're not effective. So in that case, we may actually see an enhancement of absorption of those drugs.

On the other hand, there are some drugs which need the acid to dissolve in the stomach. An example of that would be ketoconazole or itraconazole, which are two antifungal drugs. When those drugs go into the stomach, they need the acid to dissolve and unless they dissolve, they don't get absorbed. So in that case, a proton pump inhibitor will reduce the absorption of the antifungal agent, possibly leading to failure of the antifungal therapy.