CYP2D6 substrates

Snyder R, Sangar R, Wang J, Ekins S. Three dimensional quantitative structure activity relationship for CYP2D6 substrates. Quant Struct Act Relationship 2002 21 357-68. 

FIGURE 4.13 Structures of the CYP2D6 substrates, amitriptyline, codeine, haloperidol, and propranolol, and their metabolites. 

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.

Many participants expressed that there is more willingness to stratify on the basis of pharmacogenetics and pharmacogenomics for safety than for efficacy. For example, it was felt that for a CYP2D6 substrate (confirmed by in vitro and Phase I data), a stratified... 

Lewis DF, Eddershaw PJ, Goldfarb PS, Tarbit MH. 1997. Molecular modelling of cytochrome P4502D6 CYP2D6) based on an alignment with CYP102 structural studies on specific CYP2D6 substrate metabolism. Xenobiotica 27 319-339. 

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

Furthermore, as already discussed, important ethnic variations exist in the metabolic activity of both CYP3A4 and 2D6 and caution is needed when administering buspirone to Asians who are more likely to be slow metabolizers of CYP2D6 substrates and may also be on other medications that further inhibit CYP2D6 activity. 

Hamelin, B.A., Bouayad, A., Methot, J., Jobin, J., Desgagnes, P., Poirier, R, Allaire, J., Dumesnil, J., and Turgeon, J. (2000) Significant interaction between the nonprescription antihistamine diphenhydramine and the CYP2D6 substrate metoprolol in healthy men with high or low CYP2D6 activity. Clin Pharmacol Ther 67 466 77. 

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. 

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