The CYP2D6 Polymorphism

Varsaldi, F., MigUo, G., Scordo, M.G., et al. (2006) Impact of the CYP2D6 polymorphism on steady-state plasma concentrations and clinical outcome of donepezil in Alzheimer s disease patients. Eur. J. Clin. Pharmacol., 62, 721-726. 

It was the identification of a group of subjects unable to metabolize debrisoquine (118,119), resulting in a potentially life-threatening drop in blood pressure, which lead to the identification of the CYP2D6 polymorphism (120). Debrisoquine is metabolized specifically by CYP2D6 (121) to produce 4-hydroxy debrisoquine. 

Amphetamines and Phenethylamines. Deficiency in the p-hydroxylation of amphetamine was one of the observations that led to the discovery of the CYP2D6 polymorphism (Bring et al. 1970 Smith 1986). A single oral administration of the radiolabelled enantiomers of amphetamine to three volunteers with subsequent analysis of urine indicated that about 5 percent of (+)-amphetamine was converted to p-hydroxyamphetamine in two subjects but to a much less extent in the third subject, who was later found to have CYP2D6 deficiency (Smith 1986). The main excretion product was unchanged amphetamine (although the extent of excretion is known to be pH dependent), and the major metabolites were products of side... 

EM), and ultrarapid (UM) metabolizer genotypes. The figure shows that the amount of dose adaptation varies among substrates, and that clinically relevant differences in dosages exist for some antidepressants, whereas others are only slightly influenced by the CYP2D6 polymorphism. 

Brockmoller J, Kirchheiner J, Schmider J, et al. The impact of the CYP2D6 polymorphism on haloperidol pharmacokinetics and on the outcome of haloperidol treatment. Clin Pharmacol Ther 2002 72(4) 438-52. 

Rostami-Hodjegan, A., M.S. Leonard, H.F. Woods, and G.T. Tucker (1998). Meta-analysis of studies of the CYP2D6 polymorphism in relation to lung cancer and Parkinson s disease. Pharmacogenetics 8, 227-238. 

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