A4

Carbamazepin, hyperforin, modafinil, oxcarbazepin, phenobarbital, phenytoin

Efavirenz, dexamethasone, lovastatine, oxybutynin, rifabutin, rifampicin

St. John's wort, Echinacea, green tea

charcoal-broiled food that contain polyaromatic carbohy-drogens most effectively induce CYP1A2. As these enzymes are involved in biotransformation of many therapeutic agents, patients take enzyme inducers that quickly metabolize a wide range of concomitantly administered drugs. Depending on the therapeutic range, dosages must be increased to avoid the risk of loss of therapeutic effects (Fig. 1). One example is the combination of ► quetiapine and carbamazepine. Quetiapine blood levels will markedly decrease when combined with carbamazepine. Therefore, this combination is not recommended. It must also be considered that doses have to be reduced after discontinuation of inducers. Decreased enzyme activity may lead to high drug concentrations and thus bear the risk of intoxications (Fig. 1). The latter has been reported in patients who underwent treatment with the antipsychotic drugs olanzapine or clozapine after discontinuation of smoking. For drugs that are converted to active or toxic metabolites, ► enzyme induction may result in enhancement of the activity of the affected drug. An example is the induction of primidone metabolism by ► phenytoin, which results in increased concentrations of the active metabolite phenobarbital.

Enzyme Inhibition

► Enzyme inhibition is rather common in psychotropic drugs (Lynch and Price 2007). Among the five selective serotonin reuptake inhibitors, ► paroxetine, ► fluoxetine, and ► fluvoxamine are potent inhibitors of CYP enzymes (Table 4). Combining two drugs of which one is an inhibitor and the other a substrate of the same enzyme, the concentration of the substrate will increase as shown in Fig. 2. Whether this increase has clinical consequences by inducing a toxic reaction, will depend on the therapeutic range of the drug. This may be controlled by determining drug concentrations in blood through therapeutic drug monitoring (TDM). Pharmacokinetic drug interactions are therefore an important indication to use TDM (Baumann et al. 2004; Bengtsson 2004). Considering the enzymes involved in the metabolism, it may be predicted whether plasma concentrations increase after the addition of another drug (Fig. 2). Using TDM and dose reduction it is possible to avoid toxic reactions. TDM may also be useful after discontinuation of the inhibiting drug, as plasma concentrations may decrease to low levels, leading to the risk of loss of action. Considering the pharmacokinetic profile of the combined drugs, it is possible to use interacting drugs safely. However, prediction is not always easy. Psychoactive drugs can be metabolized by a single enzyme such as ► atomoxetine by CYP2D6 or by several enzymes such as amitriptyline by CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. A drug can also be a substrate and inhibitor of the same enzyme such as paroxetine for CYP2D6 or fluvoxamine for CYP1A2. Therefore, it is advisable to control drug concentrations in blood to measure the effect of the co-medication. This is especially useful when combining a drug with a CYP inhibitor (Hiemke 2008). The therapeutic index of the affected drugs is also of great concern. In combination with an inhibiting or inducing drug, plasma levels of a given substrate are more likely to reach toxic or subtherapeutic values when the substrate has a narrow therapeutic index. This is of importance for ► tricyclic antidepressants, clozapine, and also some new antipsy-chotic drugs (e.g., loss of action of quetiapine after addition of St John's wort).

Drug Interactions. Fig. 1. Pharmacokinetic behavior of a drug before and after addition of a drug metabolizing enzyme inducer and before and after dose increase.

Drug Interactions. Table 4. Inhibitors of CYP isoenzymes.

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