Carbamazepine P450 inhibition

Transient elevation of carbamazepine plasma levels is evident with cimetidine (due to the latter s cytochrome P450 inhibition capacity). 

Phenobarbital, phenytoin, primidone, and carbamazepine are potent inducers of cytochrome P450 (CYP450), epoxide hydrolase, and uridine diphosphate glucuronosyltransferase enzyme systems. Valproic acid inhibits many hepatic enzyme systems and displaces some drugs from plasma albumin. 

CYP 450 Drugs that induce liver enzymes (eg, phenytoin, carbamazepine, phenobarbital) increase the metabolism and clearance of zonisamide and decrease its half-life. Concurrent medication with drugs that induce or inhibit CYP3A4 would be expected to alter serum concentrations of zonisamide. Zonisamide is not expected to interfere with the metabolism of other drugs that are metabolized by cytochrome P450 isozymes. 

All SSRIs (e.g., Feonard et ah, 1997) and in particular fluoxetine, Fluvosamine and paroxetine are metabolized by hepatic cytochrome P450 enzymes. Therefore, it is important to be aware of the possibility that the therapeutic or toxic effects of other medications metabolized by the cytochrome P450 isoenzyme system can be increased. Substantial inhibition of these isoenzymes converts a normal metabolizer into a slow metabolizer with regard to this specific pathway. Inhibition of the hepatic oxidative isoenzymes has been associated with a reduction, to a varying extent, in the clearance of many therapeutic agents, including the TCAs, several neuroleptics, antiarrhythmics, theophy-lene, terfenadine, benzodiazepines, carbamazepine, and warfarin (for a complete list, see Nemeroff et ak, 1996). 

Aripiprazole is hepatically metabolized, mainly by two cytochrome P450 enzymes CYP 2D6 and CYP 3A4. Therefore, dosage adjustments are necessary when this medication is given with other medications that either inhibit or induce these enzymes. For example, the dose of aripiprazole should be halved when this medication is given with ketoconazole, a CYP 3A4 inhibitor, or at least decreased when given with fluoxetine, a CYP 2D6 inhibitor. When aripiprazole is given with CYP 3A4 inducers such as carbamazepine, the dose should be doubled. 

Carbamazepine induces hepatic cytochrome P450 (CYP) enzymes, which may reduce levels of other medications. Through the mechanism of hepatic enzyme induction, carbamazepine therapy can lead to oral contraceptive failure therefore, women should be advised to consider alternative forms of birth control while taking carbamazepine. Similarly, use of medications or substances that inhibit CYP 3A3/4 (discussed in Chapter 1) may result in significant increases in plasma carbamazepine levels. 

Erythromycin inhibits a cytochrome P450 isoenzyme and impairs the metabolism of theophylline, warfarin, carbamazepine and methylprednisolone. The mean reduction in drug clearance is 20-25%. 

Adverse effects include nausea, headache, diarrhoea, constipation and rash but are uncommon. Omeprazole inhibits the 2C family of the cytochrome P450 system, decreasing the metabolism of warfarin, diazepam, carbamazepine and phenytoin, and enhancing the action of these drugs (but inhibition is less than with cimetidine). 

Special attention is needed when new medications are prescribed to CSA-treated patients. CSA is extensively metabolized by the cytochrome P450 hver microsomal enzyme system [2, 3], and consequently drugs that interfere with this pathway can cause important changes in CSA blood levels (Table 3). Compounds inhibiting P450 enzymes, such as ketoconazole, erythromycin, verapamil, and diltiazem increase concentration of parent CSA and may cause acute nephrotoxicity. On the other hand, drugs that increase P450 enzyme activity, such as phenobarbital, carbamazepine and... 

Valproic acid is an enzyme inhibitor that can inhibit specific cytochrome P450 isozymes, epoxide hydrolase, and UGT isozymes. The addition of valproic acid to phenobarbital results in a 30% to 50% decrease in the clearance of phenobarbital and potential toxicity if the dose of phenobarbital is not reduced. Valproic acid may increase concentrations of 10,11-carbamazepine epoxide without affecting concentrations of the parent drug via inhibition of epoxide hydrolase. Valproic acid is also a potent inhibitor of lamotrigine, via inhibition of UGT enzymes, and can result in a doubling of the half-life of lamotrigine. ... 

Inhibits P450—possible drug interactions, including carbamazepine and phenytoin. 

Most abundant isoform wide substrate range inhibited by cimetidine, macrolides, azoles, and ethanol (acute) induced by general P450 inducers such as carbamazepine, phenobarbital, phenytoin, and rifampin and by ethanol (chronic). 

Concomitant use of nephrotoxic drugs (eg, aminoglycosides, amphotericin B, vancomycin) with cyclosporine leads to enhanced nephrotoxicity. Diltiazem, ketoconazole, and verapamil inhibit the metabolism of cyclosporine, enhancing its toxic effects unless dosage is reduced. Carbamazepine induces cytochrome P450 and reduces both the therapeutic and the toxic effects of the immunosuppressant drug. The answer is (A). 

In vitro studies found quinupristin/dalfopristin inhibited the cytochrome P450 isoenzyme CYP3A4-mediated metabolism of docetaxel, tamoxifen, and terfenadine. Quinupristin/dalfopristin is predicted to raise the levels of other drugs ineluding antiarrhythmics (disopyramide, lidocaine, quinidine), antiretrovirals (such as delavirdine, indinavir, nevirapine, ritonavir), astemizole, carbamazepine, cisapride, methyl-prednisolone, paclitaxel, statins (but see Lipid regulating drugs , (p.l086)), and vinca alkaloids. More study is needed. 

It would appear that diltiazem and verapamil inhibit the metabolism of carbamazepine by the cytochrome P450 isoenzyme CYP3A4, thereby reducing its loss from the body and increasing serum levels. In contrast, car-... 

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. 

It seems probable that clarithromycin, erythromycin and troleandomycin, and to a lesser extent some of the other macrolides, slow the rate of metabolism of the carbamazepine by the cytochrome P450 isoenzyme CYP3A4 so that the anticonvulsant accumulates within the body." " Telithromycin is predicted to interact similarly." It was suggested that the carbamazepine toxicity seen with roxithromycin may have been mediated by P-glycoprotein inhibition, which occurred as a result of an interaction between roxithromycin and atorvastatin. 

Both drugs are metabolised by the cytochrome P450 isoenzyme CYP3A4. Nefazodone is known to inhibit CYP3A4, whereas carbamazepine is a potent inducer of CYP3A4. Hence concurrent use reduces carbamazepine metabolism, leading to raised levels, and increases nefazodone levels, leading to lowered levels. 

Omeprazole may inhibit the oxidative metabolism of single doses of carbamazepine. However, when carbamazepine is taken continuously it induces its own metabolism by the cytochrome P450 isoenzyme CYP3A4, thereby possibly opposing the effects of this interaction. ... 

Not fully understood, but in vitro studies indicate that remaeemide inhibits the cytochrome P450 isoenzyme CYP3A4, which in practice would be expected to result in a reduction in the metabolism of the carbamazepine resulting in an increase in its serum levels. Remaeemide appears to inhibit C YP2C9 to a lesser extent, which is reflected in a smaller interaction with phenytoin. Valproate is metabolised by glucuronidation and is therefore unaffected. ... 

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