Caucasians, CYP2D6 polymorphisms

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. 

Unexpected neurotoxicity from amphetamine and its analogs (e.g. 3,4 methylenedioxymethamphetamine, also known as ecstasy ) as well as interactions with other drugs subject to CYP2D6 polymorphism would likewise be expected to occur more frequently among Africans and Caucasians than in Asians.(112)... 

CYP2D6 polymorphism has differential prevalence and effect among population subgroups. For example, CYP2D6 polymorphisms associated with slow drug metabolism are found in approximately 5% to 10% of Caucasians and 1% to 3% of Hispanics, African Americans, and Asian Americans [10]. 

Possibly the most studied genetic polymorphism is that associated with CYP2D6. At least 17 variant alleles of this enzyme have been identified, most being associated with a deficiency in the ability to carry out CYP2D6-mediated oxidation reactions. Approximately 7% of the Caucasian population is CYP2D6 deficient,... 

Genetic polymorphism in debrisoquin 4-hydroxylation by CYP2D6 in a Caucasian population. The semilog frequency... 

CYP2D6 was perhaps the first and best characterized of the polymorphic P450 enzymes. The PM phenotype is characterized clinically by a marked deficiency in the metabolism of certain compounds, which can result in drug toxicity or reduced efficacy. The prevalence of the PM phenotype shows marked ethnic differences, with a mean value of approximately 7% in Caucasian populations (97) but 1 % or less in Orientals (98). There are many different CYP2D6 alleles identified, including some that result in an ultrarapid metaboliser phenotype (99), and the typically applied genotyping methodologies are 90% predictive of phenotype (100). 

Drugs that are metabolized by the cytochrome P-450 (CYP) isoenzymes CYP2D6, CYP2C9, and CYP2C19 also exhibit genetic polymorphisms. An example of CYP2D6 metabolism is debrisoquine. In about 5-10 /o of Caucasians in North America and Europe and about 1% of Asians, 4-hydroxylation of debrisoquine is reduced, and such individuals are at increased risk for toxicity (orthostatic hypotension). Beta blockers (metoprolol and timolol), antiarrhythmic drugs (encainide and flecainide), tricyclic antidepressants... 

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