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FIGURE 8-12. Predicted plasma concentration changes from the coadministration of an inhibitor of the metabolism of drug A.
In contrast to the delayed effects of an inducer on drug A, the addition of an inhibitor causes an immediate increase in the plasma concentration of drug A (see Figure 8-12). This increase occurs as a result of a competitive inhibition of the relevant hepatic enzyme. Drug A's plasma concentration rises to a new steady state consistent with a change in its clearance. The time required to achieve the new steady state is greater than the time to achieve the initial steady state, because the half-life is now prolonged relative to its original value. The full effect of an inhibitory interaction may not be realized until the inhibitor also reaches a steady state, because the degree of inhibition will also depend on the concentration of the inhibitor (Houston 1994; von Moltke et al. 1994, 1995).
Drug interactions are graded phenomena. The degree of interaction depends on the concentration of interacting drugs and, therefore, on the dose and timing of administration. Drug interactions are most likely to be detected when therapy with an interacting drug is initiated or discontinued. The clinical significance will depend on the particular drugs involved, the physiological state of the patient, the presence of concurrent illness, and other factors. Drugs with a narrow concentration range over which therapeutic effects are present without incurring toxicity are more likely to be involved in clinically significant drug interactions. These drugs include theophylline, some antiepileptic drugs, and antiarrhythmics (see Table 8-1).
When selecting a specific drug from a class of drugs to treat mental illness, its efficacy, safety, cost, and history of response are pertinent considerations. The introduction of the SSRIs has emphasized the critical importance of also considering potential drug interactions (Brosen 1996). Some of these antidepressants have been shown in vitro and in vivo to be potent inhibitors of specific cytochrome P450 isoenzymes (Crewe et al. 1992; Nemeroff et al. 1996; von Moltke et al. 1994, 1995). The most thoroughly studied reaction is the competitive inhibition of CYP2D6. Pharmacokinetic studies in healthy volunteers have provided a rank order of the potency for increasing the plasma concentration of model substrates. Case reports in patients have confirmed the existence of some interactions, and many others remain theoretical possibilities. Table 8-4 provides an overall ranking of the cytochrome P450 inhibitory potential of the antidepressants based on both in vitro and in vivo data. The rational selection of an antidepressant should include consideration of its potential enzyme inhibition when therapy is to be combined with substrates listed in Table 8-1, which may be inhibited by the specific antidepressant. Reviews (Harvey and Preskorn 1996; Nemeroff et al. 1996) describe the specific in vivo reports in more detail. While numerous interactions are possible, their clinical significance is a topic that continues to be debated (DeVane 2006; Preskorn and Werder 2006). Compensatory mechanisms and patterns of practice that minimize the expression of significant interactions include parallel pathways of drug elimination, dose dependence of inhibition and induction, initiating dosage at lower starting doses, and careful attention to patient response (DeVane 2006). Although some interactions have an unequivocal high likelihood for adverse events (e.g., drug combinations that can result in a serotonin syndrome), severe adverse interactions appear to be rare events.
TABLE 8-4. Newer antidepressants and cytochrome P450 (CYP) enzyme inhibitory potential Drug CYP1A2 CYP2C9/19 CYP2D6 CYP3A4
Citalopram 0 0+ 0
Escitalopram 0 0 0 0
Fluoxetine (metabolite) 0 ++ ++ + + (++++) ++ (+++)
Mirtazapine 0 0 0 0
Note. 0 = unknown or insignificant; + = mild and usually insignificant; ++ = moderate and possibly significant; +++ = moderate and usually significant; ++++ = potent.
Source. In vivo and in vitro results: Crewe et al. 1992; Nemeroff et al. 1996; von Moltke et al. 1994, 1995. The selection of a drug based on its cytochrome P450 inhibitory potential should not be limited to the newer antidepressants (see Table 8-4). Combining any two drugs that are substrates for the same enzyme increases the likelihood of competitive enzyme inhibition. All of the substrates listed in Table 8-1 are potential inhibitors. For example, nortriptyline, desipramine, and thioridazine are potent inhibitors of CYP2D6. In vitro methods using microsomal incubations to predict in vivo interactions have appeared and are based on accepted pharmacokinetic principles (Gillette 1971; Houston 1994; von Moltke et al. 1994, 1995). These screening techniques are now used extensively in the pharmaceutical industry in drug development. The knowledge of isoenzyme-specific metabolism of new and established drugs is expanding rapidly and holds promise for further enabling the selection of combined pharmacotherapy based on pharmacokinetic principles.
The increasingly recognized role of drug transporters in the disposition of psychoactive drugs has led to the proposition that inhibition or induction of transporter activity may be involved as a mechanism of drug interactions. Risperidone and its metabolite paliperidone, along with some antidepressants, have been shown in vitro to be inhibitors of P-gp (Doran et al. 2005; Zhu et al. 2007). Reports of clinically significant interactions related to these effects have yet to emerge.
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