Cytochrome P450 enzymes poor metabolizers

Figure 2. Relative potency of the various cytochrome P450 enzymes in the metabolism of commonly prescribed proton pump inhibitors (PPi) is noted. Patients with genetic polymorphisms of the CYP2C19 pathway (poor metaboUzers) utilize the CYP3A4 pathway (dotted line) for PPi metabolism. Calcineurin inhibitors (CNI) also use the CYP3A4 pathway for their metabolism. As a result, the "poor metaboUzers" are at risk to develop elevated CNI levels when concurrently receiving a PPI. In contrast, rabeprazole is safe as it has a "non-enzymatic"pathway for its metabolism, avoiding an interaction with the CNI.

Variability in metabolism A subset (approximately 7%) of the population is devoid of CYP2D6, the enzyme responsible for the formation of the 5-hydroxymethyl metabolite of tolterodine. The identified pathway of metabolism for these individuals ( poor metabolizers ) is by dealkylation via cytochrome P450 3A4 (CYP3A4) to A/-dealkylated tolterodine. The remainder of the population is referred to as extensive metabolizers. Pharmacokinetic studies revealed that tolterodine is metabolized at a slower rate in poor metabolizers than in extensive metabolizers this results in significantly higher serum concentrations of tolterodine and in negligible concentrations of the 5-hydroxymethyl metabolite. 

These differences in clinical response and pharmacokinetics have been attributed to ethnic differences in drug metabolism mediated through the cytochrome P450 microsomal enzyme system, which is responsible for the metabolism of most of the older psychotropic medications, including typical antipsychotics and TCAs (Lin et al. 1993 Silver et al. 1993). Earlier studies showed that Caucasians were more likely than Asians and African Americans to be poor metabolizers of psychotropic medication, a finding inconsistent with clinical experience, because poor metabolizers should require less medication. However, new mutations have recently been discovered in the enzymatic systems of the latter groups that are intermediate in the rate of metabolism. Thus, up to 47%-70% of African Americans and Asian Americans may be slow metabolizers, which could account for the higher incidence of side effects (Mendoza et al. 1999). 

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