|
|
|
|
|
|
|
pathways can occur if there is a low metabolism by a particular genetically controlled pathway. An example of this is the metabolism of paroxetine by CYP 2D6, and although there are some differences in the steady-state levels between ultrafast and poor metabolizers, an alternative parallel metabolic route protects the poor metaboliser (PM) against dramatic increases in drug levels and adverse reactions [34]. Metabolic pathways (e.g., N-dealkylation) may be catalyzed by multiple enzymes, the extent depending on the relative amounts of enzymes present, making identification of specific mechanisms difficult. Thus, the gross differences in clearance, which could be expected in poor metabolizers for certain drugs, are often not found. In reality, the largest variability in enzyme levels in the liver occurs for CYP 3A4, which is not under genetic polymorphic control and, with the highest levels in the liver, can produce large variations in steady-state levels in clinical trials [35]. Thus, there is concern in the pharmaceutical industry that the regulatory authorities, sometimes with their own laboratories undertaking limited investigations, will view polymorphism as a box-checking exercise and beneficial drugs will be delayed or denied authorization because they are metabolized by a polymorphic enzyme [23]. |
|
|
|
|
|
|
|
|
There is another problem. What will the prescribing clinician do with this information? The knowledge that certain co-administered drugs are metabolized by the same enzyme and may produce adverse reactions is important information for the doctor, and in vitro metabolic studies will focus attention towards these potential problems. However, the possibility of altering the dosage in poor or ultrafast metabolizers or certain ethnic groups, e.g., is practically difficult: How would this information be generally available? There have been suggestions that all patients should be genotyped if they are to be prescribed certain drugs [36]. Although this may be possible within the hospital, in general practice it would not be feasible. There are also the implications of civil liberty. If this information is available to doctors or pharmacists, for example on smart identity cards, it would also become available to life insurance companies. They may decide to decline insurance coverage for a subject who is an ultra-fast metaboliser (UFM) to CYP 2D6 since this also increases the risk of liver cancer [37] or a PM to N-acetyltransferase, which increases the risk of bladder cancer [38] or a PM to CYP 2D6 and has a family history of Parkinson's disease [39]. The ramifications of these actions must be thought about carefully and it seems illogical to embark on detailed additional studies with already over stretched resources if the results are difficult to interpret or put into effect, and the methods of effecting change have not been properly considered. |
|
|
|
|
|
|
|
|
There is increasing awareness that a knowledge of animal kinetics and metabolism is of little value unless it can be extrapolated to humans. This is important |
|
|
|
|
|