CYP2D6  metabolizes many of the cardiovascular and neurologic drugs in use toaday.  Study of CYP2D6 has led to understanding  the failure of codeine to relieve pain in some patients.  Codeine is actually a pro-drug that is converted to  morphine.  Codeine itself is much less active as an analgesic, but causes  nausea and other adverse effects.  The absence of cytochrome P450 2D6 in 7% of Caucasians means that these individuals cannot metabolize codeine to the active metabolite, morphine, and therefore will get little, if any, pain relief from codeine.{Caraco}  However, they will experience codeine’s  adverse effects, particularly if the dose is increased in the futile attempt to obtain pain relief.
   Thirty percent of Ethiopians studied had multiple copies of the 2D6 gene (up to 13) and increased eynzyme activity resulting in ultrarapid metabolism.{Akilillu}  Ultra-rapid metabolism results in lower blood levels  following a standard dose of any drug metabolized by this enzyme.  Therefore these patients may have an inadequate response to standard dosages of  -blockers, narcotic analgesics, or antidepressants and may require higher dosages for clinical effectiveness.
   Several commonly used medications inhibit CYP2D6.  These include quinidine{Branch} as well as haloperidol and  some other antipsychotics.{Shin 1999},{Shin 2001}  The well-described pharmacokinetic interaction between selective serotonin reputake inhibitor (SSRI) antidepressants and tricyclic  antidepressants appears to be due to the fact that fluoxetine and paroxetine are both  potent inhibitors of CYP2D6 {Bergstrom},{Leucht} and render patients metabolically equivalent to people who do not have the enzyme.  This increases the plasma levels of tricyclic antidepressants and increases the potential for side effects.   In contrast, patients co-prescribed fluoxetine or paroxetine with codeine may experience no analgesic benefit, since codeine requires CYP2D6 for metabolism to morphine.

Caraco Y, Sheller J, Wood AJ. Pharmacogenetic determination of the effects of codeine and prediction of drug interactions. J Pharmacol Exp Ther 1996; 278(3):1165-1174.
Bergstrom RF, Peyton AL, Lemberger L. Quantification and mechanism of the fluoxetine and tricyclic antidepressant interaction. Clin Pharmacol Ther 1992; 51(3):239-248.
Leucht S, Hackl HJ, Steimer W, Angersbach D, Zimmer R. Effect of adjunctive paroxetine on serum levels and side-effects of tricyclic antidepressants in depressive inpatients. Psychopharmacology (Berl) 2000; 147(4):378-383.
Aklillu E, Persson I, Bertilsson L, Johansson I, Rodrigues F, Ingelman-Sundberg M. Frequent distribution of ultrarapid metabolizers of debrisoquine in an ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles. J Pharmacol Exp Ther 1996; 278(1):441-446.
Branch RA, Adedoyin A, Frye RF, Wilson JW, Romkes M. In vivo modulation of CYP enzymes by quinidine and rifampin. Clin Pharmacol Ther 2000; 68(4):401-411.
Shin JG, Kane K, Flockhart DA. Potent inhibition of CYP2D6 by haloperidol metabolites: stereoselective inhibition by reduced haloperidol. Br J Clin Pharmacol 2001; 51(1):45-52.
Shin JG, Soukhova N, Flockhart DA. Effect of antipsychotic drugs on human liver cytochrome P-450 (CYP) isoforms in vitro: preferential inhibition of CYP2D6. Drug Metab Dispos 1999; 27(9):1078-1084.