Desipramine CYP2D6 substrate

MODAFINIL ANTIDEPRESSANTS - clomipramine, desipramine - CYP1A2 substrates, CYP2C9 substrates, above T of plasma concentrations of TCAs in a subset of the population (7-10% of Caucasians) who are deficient in CYP2D6 CYP2C19 provides an ancillary pathway for the metabolism of domipramine and desipramine. Modafinil inhibited CYP2C19 reversibly at pharmacologically relevant concentrations i dose of TCAs is often necessary... 

Desipramine is extensively metabolised by CYP2D6, and can be used as a probe drug for assessment of the effect of drugs on this isoenzyme in extensive metabolisers (see Genetic factors , (p.4)). It was concluded that atomoxetine, even at the maximum recommended dose, does not cause clinically relevant inhibition of CYP2D6 in vivo, and so will not affect the pharmacokinetics of other CYP2D6 substrates. For a list of C YP2D6 substrates, see Table 1.3 , (p.6). 

The manufacturers note that steady-state darifenacin 30 mg once daily increased the AUC of imipramine by 70% and increased the AUC of its active metabolite, desipramine, 2.6-fold in a study in healthy subjects. Because of these changes, the manufacturer recommends caution with tricyclic antidepressants and other CYP2D6 substrates that have a narrow therapeutic window. They name flecainide and thioridazine (see Table 1.3 , (p.6), for a list). 

Drug-drug interactions The inhibitory effect of bupropion on CYP2D6 metabolism has been previously demonstrated in vivo, for example by inhibition of dextromethorphan metabolism (SEDA-30, 20). An in vitro study using desipramine as substrate has suggested that this effect is due to the metabolites erythrohydrobupropion and threohydrobupropion, which were much more potent inhibitors of CYP2D6 than hydroxybupropion or bupropion itself [71 ]. 

Bupropion is metabolized primarily by CYP2B6, and its metabolism may be altered by drugs such as cyclophosphamide, which is a substrate of 2B6. The major metabolite of bupropion, hydroxybupropion, is a moderate inhibitor of CYP2D6 and so can raise desipramine levels. Bupropion should be avoided in patients taking MAOIs. 

There is a wide choice of dmgs that are substrates for CYP2D6, but sparteine, debrisoquine, desipramine, dextromethorphan, and metoprolol have been used most frequently, both in vitro and in vivo. One advantage for in vivo drug-drug interaction studies is that most of the substrates were identified in the clinic rather than by the use of a battery of in vitro methods. 

Initiate therapy of these drugs, particularly those with a narrow therapeutic index, at the lowest effective dose. Interaction is likely to be important with substrates for which CYP2D6 is considered the only metabolic pathway (e.g. hydrocodone, oxycodone, desipramine, paroxetine, chlorpheniramine, mesoridazine, alprenolol, amphetamines, atomoxetine)... 

A recent study prospectively genotyped all patients for the CYP2D6 gene and excluded poor metabolizers to enhance patient safety (129). The study was a randomized, double-blinded comparison of lamotrigine with desipramine in patients with unipolar depression. Desipramine is a substrate for CYP2D6 and poor me-tabolizers of this enzyme have serum desipra-... 

Atomoxetine did not aiter desipramine pharmacokinetics and wouid therefore not be expected to affect other substrates of CYP2D6. Atomoxetine did not aiter midazolam pharmacokinetics and wouid therefore not be expected to affect other substrates of CYP3A4. Antacids and omeprazole do not alter atomoxetine bioavaiiabiiity. 

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