Ultrarapid Metabolizer

Cytochrome P450 2D6 Extremely high activity in about 2% of Caucasian populations and completely deficient activity in about 7%. Inefficiency in ultrarapid metabolizers and extremely heavy effects in poor metabolizers for more than 50 drugs. A few drugs requiring bioactivation by CYP have low efficacy in poor metabolizers (example codein is activated to morphine via CYP2D6). 

UDP-Glucuronyl Transferase Ultrarapid Metabolizer Unstable Angina Unwanted Effects UPR... 

Aklillu, E., Persson, I. et al. (1996). Frequent distribution of ultrarapid metabolizers of debriso-quine in an Ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles. /. Pharmacol. Exp. Ther., 278(1), 441-6. 

Saarikoski ST et al. CYP2D6 ultrarapid metabolizer genotype as a potential modifier of smoking behavior. Pharmacogenetics 2000 10(1) 5—10. 

Cramps and other reactions from excess codeine effect in 2D6 "ultrarapid metabolizers"... 

Johansson, I., et al., "Inherited amplification of an active gene in the cytochrome P450 CYP2D-locus as a cause of ultrarapid metabolism of debrisoquine," Proc. Natl. Acad. Sci. USA, 90, 11825-11829 (1993). 

Bernal, M.L., Sinues, B., Johansson, I., et al. (1999) Ten percent of North Spanish individuals carry duplicated or triplicated CYP2D6 genes associated with ultrarapid metabolism of debrisoquine. Pharmacogenetics, 9, 657-660. 

An even smaller group of patients (i.e., 0.5%) are ultrarapid metabolizers of TCAs in whom levels less than 0.5 ng/mL/mg/day develop (324). 

There is a linear relationship between dose and plasma drug levels (i.e., linear or first-order pharmacokinetics) in normal and ultrarapid metabolizers. In these individuals, the earlier equation can be used to predict the daily dose needed to produce a specific plasma drug level once TDM has been done to estimate the patient s elimination rate. In poor metabolizers, TCAs follow nonlinear pharmacokinetics (i.e., disproportionate increases in plasma drug levels with dose increases) because they lack the CYP 2D6 and must use lower affinity enzymes to metabolize these drugs. 

As a result, these subjects require twofold to threefold higher daily doses of nortriptyline (a 2D6 substrate) to achieve therapeutic plasma levels. Conversely, in these ultrarapid-metabolizing populations, the prodrug codeine (another 2D6 substrate) is metabolized much faster to morphine, often resulting in undesirable adverse effects of morphine, such as abdominal pain. 

The analysis of the molecular basis for unexpected responses of ultrarapid CYP2D6 metabolizers to codeine follows a similar line of reasoning. The ultrarapid metabolizers have enhanced capacity to metabolize codeine and hence may exhibit exaggerated responses, such as abdominal cramping, fuzzy vision and disorientation.(113) Because ultrarapid metabolizers occur more frequently among Hispanic, African and Saudi Arabian than Asian populations,(106) the former groups would be more likely to experience exaggerated responses to codeine. 

P. Dalen, C. Fregnell, M.-L. Dahl, F. Sjoqvist, Quick Onset of Severe Abdominal Pain after Codeine in an Ultrarapid Metabolizer of Debrisoquine , Ther. Drug Monit., 19, 543-544 (1997). 

Kawanish C, Lundgren S, Agren H, Bertilsson L. Increased incidence of CYP2D6 gene duplication in patients with persistent mood disorders ultrarapid metabolism of antidepressants as a cause of nonresponse. A pilot study. Eur J Clin Pharmacol 2004 59 803-807. 

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