ABSTRACT
In 1969, Alexanderson et al. (1969) provided the first direct evidence from a twin study that the metabolic clearance of nortriptyline is influenced by genetic factors. Mahgoub et al. (1977) and Eichelbaum et al. (1979) have discovered that the metabolism of debrisoquine and sparteine is polymorphic, and it is later shown that these drugs are metabolized by a common enzyme, that is, CYP2D6. To date, CYP2D6 is one of the most investigated CYPs in relation to polymorphism that accounts for only a small percentage of all hepatic CYPs (–2%–4%); however, it metabolizes –25% of currently used drugs in the human liver (Cascorbi 2003; Gardiner and Begg 2006; Ingelman-Sundberg 2005; Ingelman-Sundberg et al. 2007; Zhou et al. 2008). Typical substrates for CYP2D6 are largely lipophilic bases and include some antidepressants, neuroleptics, antiarrhythmics, antiemetics, β-blockers, and opioids. Most CYP2D6 substrates are bases containing a basic nitrogen atom 5–10 Å from the site of metabolism (Marechal et al. 2008). CYP2D6 appears to have high affinity and low capacity for its substrates and becomes saturated at relatively low concentrations. The primarily hepatic expression of this enzyme governs first-pass metabolism after oral drug administration, whereas the low level of its intestinal expression does not appear to be important. In contrast to other drug-metabolizing CYPs (e.g., 2C9, 2B6, and 3A4), CYP2D6 is generally not regulated by many known environmental agents and is not inducible by common known CYP inducers such as steroids and rifampin. CYP2D6 is subject to inhibition by a number of drugs, resulting in clinically significant drug interactions.
