CYP enzymes inducers

Carbamazepinewasfound to decrease the plasma levels of phenothiazines by as much as 50% (described with chlorpromazine, perphenazine, and fluphenazine). It has been reported to decrease the serum levels of clozapine by about60-85% due to its hepatic cytochrome P450 (CYP) enzyme-inducing properties. Loxapine may induce carbamazepine metabolism. Carbamazepine has been shown to reduce the plasma levels of risperidone by as much as 50%, while it increases olanzapine clearance by 44% and reduces its half-life by 20%. Carbamazepine increases aripiprazole metabolism through CYP3A4 induction. Thus, the aripiprazoie dose should be doubled. 

Maintain plasma levels between 30 and 40 mg/L ° Taper dose if ICP well controlled for 24-48 h ° Potent CYP 450 enzyme inducer... 

Hollenberg, P.F. (2002) Characteristics and common properties of inhibitors, inducers, and activators of CYP enzymes. Drug Metabolism Reviews, 34 (1-2), 17-35. 

CYP enzymes are induced, resulting in reduced plasma drug levels. Alternatively, CYP enzymes could also undergo mechanism-based inhibition, whereby a CYP enzyme can be completely inactivated by covalent bonding to a component of the herb. Furthermore, botanicals can elicit a biphasic cellular response, whereby CYP activity may be inhibited initially, followed by induction after prolonged incubation or repeated administration. Such factors would need to be considered in future studies in order to establish the true risk of ginseng in herb-drug interactions. 

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. 

Drugs that inhibit CYP 3A4 reduce metabolism of ziprasidone concurrent treatment with ketoconazole increased blood levels of ziprasidone by approximately 40%. Carbamazepine (and possibly other enzyme inducers) may decrease ziprasidone levels by approximately 35%. Effects of ziprasidone on metabolism of other drugs have not been reported. 

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. 

Modafinil is a substrate for the cytochrome P450 (CYP) enzyme 3A4. It is also induces CYP 1A2, 2B6, and 3A4 and can decrease the serum levels and effectiveness of substrates for these enzymes. 

Alcohol, nicotine, and most anticonvulsants induce a number of CYP enzymes (39, 40). This mechanism explains why barbiturates and carbamazepine induce the metabolism of other drugs as well as their own (i.e., autoinduction ). Blood levels obtained 3 or 4 days after starting these drugs reflect the rate of elimination at that time however, levels will subsequently fall on the same dose because autoinduction results in faster elimination (i.e., a shorter half-life) as a function of continued drug administration. Therefore, early TDM of carbamazepine will overestimate the eventual concentration reached after several weeks on the drug (see the section Alternatiye T[eatm in Chapter 10). 

Drinking on a regular basis for several weeks to months can induce CYP enzymes, resulting in a lower TCA plasma concentration. Thus, subacute and subchronic alcohol consumption induces liver enzymes and causes lower plasma levels of drugs that undergo oxidative biotransformation as a necessary step in their elimination. 

Addition of a drug that can induce or inhibit the CYP enzymes responsible for the metabolism of these drugs... 

Because most antidepressants require oxidative metabolism as a necessary step in their elimination, they can be the target of a pharmacokinetic drug-drug interaction, as well as the cause. The CYP enzymes mediating the biotransformation of the various antidepressants are also shown in Table 7-30. CYP 1A2 and 3A3/4 are induced by anticonvulsants such as barbiturates and carbamazepine. As expected, coadministration of these anticonvulsants has been shown to lower plasma levels of TCAs and would be predicted to have the same effect on nefazodone, sertraline, and venlafaxine. 

Table 2B Labeling Examples of Drug-Drug Interactions (Drugs as Inhibitors or Inducers of CYP Enzymes)...

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