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Drug-metabolizing enzymes are highly regulated by chemicals in the organisms environment.
In this presentation, we'll discuss
several physiological and pathophysiological factors
that affect drug metabolism in distinct populations.
This slide lists some of the most important factors.
For the purposes of this presentation,
I'll focus on the first four of these important regulatory mechanisms:
gender, pregnancy, development and aging,
and inflammation and infection.
In most cases, the reason for this regulation is not known,
but may be related to the enzymes abilities to
catabolize physiological substrates, such as steroids,
bile acids and thyroid hormones or to synthesize bioactive metabolites,
such as hydroxylated and epoxidized carcinoids.
Regardless of the reasons,
the potential consequences for human and animal drug therapy
for susceptibility to toxicants and for drug development are clear.
As a general principle,
it's important to appreciate that none of these physiological factors
affecting drug metabolism operate in isolation.
Ultimately, the expression of an enzyme, and therefore,
the responses to drugs that it metabolizes will be an integration of
all the non-genetic factors that can control
the enzyme impinged upon the individual's genetic constitution.
So a 50% decrease in the metabolism of a given drug due to, for example,
a viral infection might not have a significant effect
on most people's response to a drug that has a good safety margin.
However, the same infection could have an adverse effect in
someone who has a predisposition to metabolize that drug early.
For example, someone who is heterozygous for
an inactivating mutation in a cytochrome P450 enzyme.