CYP2D6 inhibitors

Ekins S, Bravi G, Binkley S, Gillespie JS, Ring BJ, Wikel JH, et al. Three and four dimensional-quantitative structure activity relationship (3D/4D-QSAR) analyses of CYP2D6 inhibitors. Pharmacogenetics 1999 9 477-89. 

Use of a hERG blocker in a patient also taking CYP3A4 inhibitors (e.g. antibacterial macrolides, azole antifungals, HIV protease inhibitors) or CYP2D6 inhibitors (quinidine, halofantrine, fluoxetine, paroxetine, thioridazine, terbinafine) the hERG blocker, if mostly metabolized by these CYP isoforms, may accumulate because... 

Thioridazine Drugs that prolong the QT interval - CYP2D6 inhibitors (eg, fluoxetine, fluvoxamine, paroxetine, pindolol, propranolol)... 

Concomitant use with potential CYP2D6 inhibitors - During coadministration of potential CYP2D6 inhibitors such as quinidine, fluoxetine, or paroxetine with aripiprazole, reduce the aripiprazole dose to at least one-half of its normal dose. 

Concomitant use In children up to 70 kg body weight administered strong CYP2D6 inhibitors, initiate atomoxetine at 0.5 mg/kg/day and only increase to the usual target dose of 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and the initial dose is well-tolerated. 

Drugs that may interact with atomoxetine include albuterol, CYP2D6 inhibitors, MAOIs, and pressor agents. 

The potential for drug interactions with fosamprenavir changes when fosamprenavir is coadministered with the potent CYP3A4 inhibitor ritonavir. Because ritonavir is a CYP2D6 inhibitor, clinically significant interactions with drugs metabolized by CYP2D6 are possible when coadministered with fosamprenavir plus ritonavir. 

The most common interactions with SSRIs are pharmacokinetic interactions. For example, paroxetine and fluoxetine are potent CYP2D6 inhibitors (Table 30-4). Thus, administration with 2D6 substrates such as TCAs can lead to dramatic and sometimes unpredictable elevations in the tricyclic drug concentration. The result may be toxicity from the TCA. Similarly, fluvoxamine, a CYP3A4 inhibitor, may elevate the levels of concurrently administered substrates for this enzyme such as diltiazem and induce bradycardia or hypotension. Other SSRIs, such as citalopram and escitalopram, are relatively free of pharmacokinetic interactions. The most serious interaction with the SSRIs are pharmacodynamic interactions with MAOIs that produce a serotonin syndrome (see below). 

Elevations of TCA levels may occur when combined with CYP2D6 inhibitors or from constitutional factors. About 7% of the Caucasian population in the USA has a CYP2D6 polymorphism that is associated with slow metabolism of TCAs and other 2D6 substrates. Combination of a known CYP2D6 inhibitor and a TCA in a patient who is a slow metabolizer may result in additive effects. Such an interaction has been implicated, though rarely, in cases of TCA toxicity. There may also be additive TCA effects such as anticholinergic or antihistamine effects when combined with other agents that share these properties such as benztropine or diphenhydramine. Similarly, antihypertensive drugs may exacerbate the orthostatic hypotension induced by TCAs. 

Maprotiline (bupropion) NET > SERT inhibition (amoxapine, maprotiline) t increased release of norepinephrine, 5-HT (mirtazapine) but no effect on 5-HT (bupropion) amoxapine and maprotiline resemble TCAs (mirtazapine) amoxapine and maprotiline rarely used bupropion) sedation and weight gain (mirtazepine) Interactions CYP2D6 inhibitor (bupropion)... 

Fig. 14.1 A CYP2D6 inhibitor HypoGen pharmacophore model derived from quinidine and quinine analogs (Hutzler et a I., 2003) showing (a) the mapping of a training set compound, (b) the substrate debrisoquine...

Dezentje VO et al (2010) Effect of concomitant CYP2D6 inhibitor use and tamoxifen adherence on breast cancer recurrence in early-stage breast cancer. J Clin Oncol 28 2423-2429... 

Paroxetine 20 mg/day, a selective CYP2D6 inhibitor, was given for 12 days to 10 patients on methadone maintenance (27). Eight were genotyped as CYP2D6 homozygous extensive metabolizers and two as poor metabolizers. Paroxetine increased the steady-state concentrations of //-methadone and. V-methadone, especially in the extensive metabolizers. 

Administration of the CYP2D6 inhibitor quinidine, 200 mg/day for 2 days, to the extensive metabolizers reduced the oral clearance of venlafaxine to the level seen in poor metabolizers. Quinidine had no effect on venlafaxine clearance in subjects who were poor metabolizers before treatment. The authors suggested that poor metabolizers may be at particular risk of venlafaxine toxicity, as could subjects who take inhibitors of CYP2D6. 

The metabolism of propafenone is complex. The primary pathway involves CYP2D6, with some people having higher activity than others those with less extensive activity are more susceptible to the effects of CYP2D6 inhibitors. CYP3A4 acts as a back-up pathway. 

FLECAINIDE H2 RECEPTOR BLOCKERS Cimetidine may t flecainide levels Cimetidine inhibits CYP2D6-mediated metabolism of flecainide. Ranitidine is a much weaker CYP2D6 inhibitor Monitor PR and BP at least weekly until stable. Warn patients to report symptoms of hypotension (lightheadedness, dizziness on standing, etc.). Consider alternative acid suppression therapy... 

Desipramine and nortriptyline are the least problematic in terms of drug interaction, being weak inhibitors of CYP2D6 inhibitors. 

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