CYP2D6 Debrisoquine Sparteine Polymorphism

Polymorphic CYP2D6 was one of the first and most important drug-metabolizing enzyme pharmacogenetic traits to be characterized at the molecular (DNA) level. Polymorphisms of the CYP2D6 gene affect the metabolism of some 25% of frequently used drugs. CYP2D6 was originally named for the test drugs debri-soquine (an antihypertensive) and sparteine (an antiarrhythmic), but now dex-tromethorphan (an antitussive), a drug with fewer side effects, is favored to test for this polymorphism. The metabolic ratio of dextromethorphan/dextrorphan (the product of oxidative demethylation) is the marker of CYP2D6 activity. Four phenotypes can be separated by this method: poor metabolizers (PMs) with high ratios, homozygous and heterozygous extensive metabolizers (EMs) with lower ratios, and ultrarapid metabolizers (URMs) with extremely low ratios.

More than 80 CYP2D6 SNP variants have been identified, but five or six of these variants account for at least 95% of the variation in worldwide populations. In URMs the mutated allele is duplicated 2-13 times. The duplication (multiplication) results in 2-13 extra copies of the gene that is responsible for the increased activity.

PMs are at increased risk of toxicity from CYP2D6 substrate drugs and are more likely to have drug interactions between drugs that are metabolized by CYP2D6. URMs may not reach therapeutic levels on usual doses and may require several times the usual dose to achieve a response. Prodrugs such as codeine (which must be converted to their active form—morphine, in the case of codeine) are ineffective in PMs and may cause toxicity in URMs.

Some drug substrates of CYP2D6

Antiarrhythmics Amiodarone, encainide, flecainide, mexiletine, procainamide, sparteine

Antidepressants Imipramine, clomipramine, desipramine, amitriptyline, nortryptyline, maprotiline ß2-Adrenergic receptor Alprenolol, propranolol, timolol, bufuralol, metoprolol, blockers bunitrolol

Neuroleptics Bisperidone, perphenazine, thioridazine, zuclopenthixol

Other drugs Codeine, 4-methoxyamphetamine, paroxetine, fluoxetine, phenformin

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