Drug-metabolizing enzymes intermediate metabolizers

The mechanisms underlying hepatotoxicity from halothane remain unclear, but studies in animals have implicated the formation of reactive metabolites that either cause direct hepatocellular damage (eg, free radical intermediates) or initiate immune-mediated responses. With regard to the latter mechanism, serum from patients with halothane hepatitis contains a variety of autoantibodies against hepatic proteins, many of which are in a trifluoroacetylated form. These trifluoroacetylated proteins could be formed in the hepatocyte during the biotransformation of halothane by liver drug-metabolizing enzymes. However, TFA proteins have also been identified in the sera of patients who did not develop hepatitis after halothane anesthesia. 

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). 

The hepatic clearance of drugs with an intermediate extraction ratio (Eh, 0.3-0.6) is affected by all three physiological variables blood flow to the liver, the unbound fraction in blood and the activity of hepatic drug-metabolizing enzymes. Disease-induced changes in the disposition of these drugs is least predictable. 

A recent study has employed deuterium labeling to show that the mechanism for the oxidative N-demethylation of nicotine may involve two modes of breakdown for a proposed carbinolamine intermediate, dealkylation with formaldehyde formation and dehydration to an iminium ion.72 The formation of such an sp2-hybrid intermediate may help to explain why both a primary and substantial / -secondary deuterium isotope effect were observed for the N-deethylation of the antiarrhythmic agent, lidocaine.73 In contrast, only a primary isotope effect was observed on the rate of oxidative O-deethylation of deuterated analogs of the analgesic, phenacetin. 77 These results indicate differences in the mechanism of oxidative 0- and N-dealkylation. A final example of the use of secondary deuterium isotope effects in studying enzymes involved in drug metabolism revealed an SN-2-like transition state for the transfer of a methyl group catalyzed by catechol-O-methyl transferase.73... 

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