Cytochrome proton pump inhibitors

Cytochrome P450 2C19, also termed S-mephenytoin hydroxylase, is a mixed-function oxidase localized in the endoplasmic reticulum which is responsible for the biotransformation of S-mephenytoin, some barbiturates, almost all proton pump inhibitors such as omeprazole, diazepam and others. 

Proton Pump Inhibitors and Acid Pump Antagonists retinoid X receptor (RXR) and is also activated by various lipophilic compounds produced by the body such as bile acids and steroids. PXR heterodimerized with RXR stimulates the transcription of cytochrome P450 3A monooxygenases (CYP3A) and other genes involved in the detoxification and elimination of the... 

BA, bioavailability CL, total body clearance CrCI, creatinine clearance CYP450, cytochrome P-450 ER, extended-release IR, immediate-release LA, long-acting PPI, proton pump inhibitor Sign., significantly SR, sustained-release TD, transdermal. 

Ishizaki, T., and Horai, Y. (1999) Review article cytochrome P450 and the metabohsm of proton pump inhibitors—emphasis on rabeprazole. Aliment. Pharmacol. Ther. 13, 27-36. 

BY 1023/SK F 96022 INN pantoprazoie, a novel gastric proton pump inhibitor, potently inhibits acid secretion but lacks relevant cytochrome P450 interactions./. Pharmacol. Exp. Ther., 1990, 254(1), 129-135. 

Proton pump inhibitors can interact with other drugs by increasing gastric pH, inhibiting hepatic cytochrome... 

Figure 2. Relative potency of the various cytochrome P450 enzymes in the metabolism of commonly prescribed proton pump inhibitors (PPi) is noted. Patients with genetic polymorphisms of the CYP2C19 pathway (poor metaboUzers) utilize the CYP3A4 pathway (dotted line) for PPi metabolism. Calcineurin inhibitors (CNI) also use the CYP3A4 pathway for their metabolism. As a result, the "poor metaboUzers" are at risk to develop elevated CNI levels when concurrently receiving a PPI. In contrast, rabeprazole is safe as it has a "non-enzymatic"pathway for its metabolism, avoiding an interaction with the CNI.

Ishizaki T, Horai Y. Review article cytochrome P450 and the metabolism of proton pump inhibitors-emphasis on rabeprazole. Aliment Pharmacol Ther 1999 13 SuppI 3 27-36. 

From the studies above it appears that grapefruit juice may have a minor inhibitory effect on the metabolism of omeprazole and lansoprazole by the cytochrome P450 isoenzyme CYP3A4 (which results in the sulphone metabolites). This was suggested to be due to intestinal inhibition of CYP3A4., Grapefruit juice does not affect the metabolism (hydroxyla-tion) of the proton pump inhibitors by CYP2C19. 

Lansoprazole possibly induces cytochrome P450 isoenzyme CYP1A2 (the enzyme by which theophylline is metabolised) to a small extent, but this is unlikely to be significant unless an individual is particularly sensitive to this effect. Other proton pump inhibitors are unlikely to interact with theophylline, and so no special precautions would seem necessary on eoneurrent use. 

Tucker GT (1994) The interaction of proton pump inhibitors with cytochromes P450. Aliment Pharmacol T/ier 8(Suppl 1) 33-38... 

The answer is c. (Murray, pp 123-148. Scriver, pp 2367-2424. Sack, pp 159-175. Wilson, pp 287-317.) The electron transport chain shown contains three proton pumps linked by two mobile electron carriers. At each of these three sites (NADH-Q reductase, cytochrome reductase, and cytochrome oxidase) the transfer of electrons down the chain powers the pumping of protons across the inner mitochondrial membrane. The blockage of electron transfers by specific point inhibitors leads to a buildup of highly reduced carriers behind the block because of the inability to transfer electrons across the block. In the scheme shown, rotenone blocks step A, antimycin A blocks step B, and carbon monoxide (as well as cyanide and azide) blocks step E. Therefore a carbon monoxide inhibition leads to a highly reduced state of all of the carriers of the chain. Puromycin and chloramphenicol are inhibitors of protein synthesis and have no direct effect upon the electron transport chain. 

In the cell, electron flow in the electron transport chain must be sequential from NADH or a flavoprotein all the way to O2 to generate ATP (see Fig. 21.5). In the absence of O2, there is no ATP generated from oxidative phosphorylation because electrons back up in the chain. Even complex I cannot pump protons to generate the electrochemical gradient, because every molecule of CoQ already has electrons that it cannot pass down the chain without an O2 to accept them at the end. The action of the respiratory chain inhibitor cyanide, which binds to cytochrome oxidase, is similar to that of anoxia it prevents proton pumping by all three complexes. Complete inhibition of the b-c complex prevents pumping at cytochrome... 

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