Enzyme-related Therapeutic Approaches

Another area of active research is the development of stable low molecular weight metal complexes, which could serve as SOD mimics. Fridovich has described a complex of mangsmese (III) with desferral, which can catalyse the dismutation of superoxide anion in vitro and can protect green algae against paraquat toxicity (Beyer and Fridovich, 1989). This manganese-desferral complex was evaluated in models of circulatory shock and also found to improve survival rate (de Garavilla etal., 1992). 

Fe(II)-tetrakis-N, N, N, N (2-pytidylmethyl-2-amino-ethyl)amine (Fe-TPEN) and Fe(III)-ttis [N-(2-pyridylmethyl)2-aminoethyl]amine (Fe-TPAA) are novel iron complexes containing lipophilic and neutral ligands. 

Catalase, the antioxidant enzyme that converts hydrogen peroxide to water, has been evaluated in combination with SOD in a model of focal ischaemic stroke in the rat. Both enzymes were eonjugated with polyethylene glycol to increase the circulatory half-life. They significantly reduced inferct volume (Liu et al., 1989). 

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At present, such techniques are being used in the circadian chronomodulation of anticancer drugs (Levi et al, 1994). These therapeutic approaches are based on the observation that the antitumoral efficacy of the drugs, as welt as their toxicity for the organism, vary with 24 h periodicity. In the case of 5-FU (see chapter 11), such observations can be related to the fact that the activity of enzymes involved in the... 

The major advantage of (fractional) oral clearance as a phenotypic trait is that its value is linearly related to the enzyme s catalytic activity, provided that first-order conditions are present. This requirement, along with any safety considerations, is the main reason the dose of an in vivo probe should be as low as possible, consistent with analytical considerations. Furthermore, it is possible to directly extrapolate this type of trait measure to the disposition of other drugs whose metabolism is mediated by the measured enzyme and also to place the trait value within a therapeutic context. On the other hand, estimation of oral clearance requires multiple blood and urine collections, often over many hours, that are an inconvenience for the study subject and require considerable amounts of analytical time and effort. Because of this, simpler and less time-consuming approaches have often been used. However, it is not always appreciated that such phenotyping tests provide only an indirect measure of metabolizing activity and may be affected by factors other than the enzyme s intrinsic clearance. In addition, it is difficult to relate an indirect trait measure to parameters that are of clinical importance, such as the drug s clearance. 

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