Cytochrome P450 enzyme CYP3A4, inhibition

Rifampin is a prototype inducer of the cytochrome P450 enzyme CYP3A4. This induction of microsomal enzymes by rifampin is thought to increase the production of toxic metabolites, contributing to the potential of valproate to cause hepatotoxicity, although this clinical outcome is rare. Valproate inhibits glucuronidation of zidovudine and increased events from zidovudine are possible. 

By using in vitro preparations of human enzymes it is possible to predict those antibiotics that will adversely affect the metabolism of other drugs [110]. Such studies have shown that rifaximin, at concentrations ranging from 2 to 200 ng/ml, did not inhibit human hepatic cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and 3A4 [34], In an in vitro hepatocyte induction model, rifaximin was shown to induce cytochrome P450 3A4 (CYP3A4) [34], an isoenzyme which rifampicin is known to induce [109],... 

Amprenavir is metabolized by the cytochrome P450 enzyme system and inhibits CYP3A4. Use caution when coadministering medications that are substrates, inhibitors, or inducers of CYP3A4, or potentially toxic medications that are metabolized by CYP3A4. 

Zaleplon is primarily metabolized by aldehyde oxidase and use with inhibitors of this enzyme, such as cimetidine, may result in increased plasma concentrations of zaleplon. Zaleplon is also partly metabolized by the cytochrome P450 isoenzyme CYP3A4 and, consequently, caution is advised when zaleplon is given with drugs that are substrates for, or potent inhibitors of, this isoenzyme. Cimetidine is also an inhibitor of CYP3A4 and thus inhibits both the primary and secondary metabolic pathways of zaleplon. Use with rifampicin or other potent enzyme-inducing drugs may accelerate the metabolism of zaleplon and reduce its plasma concentrations [40]. 

SSRIs are metabolized by cytochrome p450 enzymes in the liver. Most SSRIs inhibit CYP2D6, fluvoxamine (10) inhibits CYP1A2, and fluoxetine (9) inhibits CYP3A4. Consequently, these drugs may interfere with the metabolism of a number of other agents. 

This section deals with interactions where the effects of the antibacterial are altered. In many cases the antibacterial drugs interact by affecting other drugs, and these interactions are dealt with elsewhere in this publication. Some of the macrolides and the quinolones are potent enzyme inhibitors the macrolides exert their effects on the cytochrome P450 isoenzyme CYP3A4, whereas many quinolones inhibit CYP1A2. Ri-fampicin (rifampin) is a potent non-specific enzyme inducer and therefore lowers the levels of many drugs. 

The cytochrome P450 isoenzyme CYP3A4 is the main enzyme involved in the metabolism of carbamazepine. Components of grapefruit juice are known to inhibit CYP3A4, which in this case would lead to a reduction in the metabolism of carbamazepine, and therefore an increase in levels. Preliminary in vitro and animal studies suggest that pomegranate juice may also contain components that inhibit the CYP-mediated metabolism of carbamazepine. ... 

Not fully understood. It is thought that cimetidine can inhibit the activity of the liver enzymes concerned with the metabolism of carbamazepine (such as the cytochrome P450 isoenzyme CYP3A4), resulting in its reduced clearance from the body, but the effect is short-lived because the auto-inducing effects of the carbamazepine oppose it. This would possibly explain why the single-dose and short-term studies in healthy subjects... 

It seems probable that isoniazid inhibits the activity of the cytochrome P450 isoenzyme CYP3A4, which is concerned with the metabolism of carbamazepine, causing it to accumulate in the body. Rifampicin is a potent enzyme inducer, and would be expected to negate the effects of isoniazid, and to induce the metabolism of carbamazepine. This is supported by one report, but not another. 

Paclitaxel is metabolised by the cytochrome P450 enzymes CYP2C8 and CYP3A4. Docetaxel is metabolised by CYP3A4. Protease inhibitors such as ritonavir and indinavir are known to inhibit CYP3A4, which might result in increased taxane levels and toxicity. 

Itraconazole is a known substrate and inhibitor of the cytochrome P450 isoenzyme CYP3A4, and the protease inhibitors also inhibit and share this pathway of metabolism. Thus enzyme inhibition, and competition for metabolism results in raised serum levels of both drugs. 

Calcium-channel blockers also undergo interactions due to altered metabolism. Both verapamil and diltiazem are principally metabolised by the cytochrome P450 isoenzyme CYP3A4, and also inhibit this enzyme (see Table 1.4, (p.6)). They are therefore affected by drugs that induce or inhibit CYP3A4, and also themselves interact with drugs metabolised by CYP3A4. 

Erythromycin is an inhibitor of the cytochrome P450 isoenzyme CYP3A4, which is the main enzyme responsible for the metabolism of sirolimus. Therefore erythromycin probably inhibited the metabolism of sirolimus, causing the levels to rise. 

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