Drug-metabolizing enzymes ultrarapid metabolizers

Figure 2 The impact of genetic polymorphisms (the UM, EM, IM, and PM genotypes) and the corresponding impact of enzyme induction or inhibition on exposure to a drug. Abbreviations UM, ultrarapid metabolizer EM, extensive metabolizer IM, intermediate metabolizer PM, poor metabolizer.

Ultrarapid metabolism of an active drug could mean that therapeutic levels are not reached, while poor metabolism will increase the likelihood of adverse events at normal doses because of resulting increased levels of the drug. Conversely, for prodrugs that must first be activated by CYP enzymes, ultrarapid metabolism may increase adverse effects, while poor metabolism may result in little response. 

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. 

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). 

The difference in enzyme activity that occurs due to polymorphisms results in individuals who are extensive metabolizers (with a subgroup of ultrarapid metabolizers) or poor metabolizers of drugs. Poor metabolizers have higher... 

Ultrarapid metabolizers (UMs) for individuals having higher than normal enzymatic activity. Therefore, this is the phenotype applied to people carrying multiple gene copies of the respected enzyme. That trait is dominantly inherited and allows these individuals to rapidly metabolize the drug substrates and to achieve low, and sometimes inefficient, plasma levels. 

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