CYP2D6 substrates/inhibitors

Figure 7.5 Mucosal-to-submucosal (m-s), Tapp values across human buccal culture of midazolam (CYP3A4 substrate), bufuralol (CYP2D6 substrate), tolbutamide (CYP2C9 substrate), and the nonmetabolized, high-permeability control compound caffeine (average SEM, N = 1 — 3 replicates). (Asterisk) in the presence of CYP inhibitors (CYP3A4-ketoconazole CYP2D6-quinidine CYP2C9-suphaphenazole). In all treatments integrity of the culture was verified by permeation of Lucifer yellow (< 2.0 x 10-6 cm/s). Results from internal study by Absorption Systems Company.

Drugs that may interact with darifenacin include moderate and potent CYP3A4 inhibitors, anticholinergic drugs, CYP2D6 substrates, and digoxin. 

The SNRIs have relatively fewer CYP450 interactions than the SSRIs. Venlafaxine is a substrate but not an inhibitor of CYP2D6 or other isoenzymes, whereas desvenlafaxine is a minor substrate for CYP3A4. Duloxetine is a moderate inhibitor of CYP2D6 and so may elevate TCA and other CYP2D6 substrate levels. Like all serotonergic antidepressants, SNRIs are contraindicated in combination with MAOIs. 

Amoxapine and maprotiline share most drug interactions common to the TCA group. Both are CYP2D6 substrates and should be used with caution in combination with inhibitors such as fluoxetine. Amoxapine and maprotiline also both have anticholinergic and antihistaminic properties that may be additive with drugs that share a similar profile. 

Imipramine (Ciba-Geigy) antidepressant NA-, 5HT-uptake inhibitor al-antagonist M-antagonist 5HT2A, 2D, 6, antagonist CYP2D6 substrate... 

Identification of Substrates/Inhibitors of Human Hepatic CYP2D6. 

Duloxetine is a moderately potent CYP2D6 inhibitor (intermediate between paroxetine and sertraline). Thus, duloxetine should be used with caution when CYP2D6 substrates and inhibitors are coadministered. 

Ritonavir decreases pethidine (meperidine) and increases norpethidine levels, which may possibly increase toxicity on long-term use. Similarly, ritonavir and other protease inhibitors increase buprenorphine levels. Ritonavir may increase the metabolism of morphine, and decrease the metabolism of dextropropoxyphene (CYP3A4 substrate) and tramadol or other CYP2D6 substrates (such as codeine). 

No important interactions normally appear to occur with venlafaxine and ACE inhibitors, beta blockers or diuretics, but an isolated report suggests that propranolol, particularly if it is given with other CYP2D6 substrates, may affect the metabolism of venlafaxine. 

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