Lecture 20 Enzyme Inhibition, Matching Substrates to Enzymes

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22 Apr 2012
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Lecture 20 Enzyme Inhibition, Matching Substrates to Enzymes
Pulling drug economic loss to pharma, risk for patients (toxicity), loss of developmental
costs, lawsuits.
CASE: Seldane (non-sedating antihistamine). Dangerous heart rhythm abnormalities when
taken with erythromycin or ketoconazole.
Many patients take multiple drugs at one time.
Terfenadine (Seldane, pro-drug) + CYP3A4 Fexofenadine (Allegra, active metabolite)
Antihistamine benefits
Erythromycin or ketoconazole inhibits CYP3A4, leading to buildup, accumulation of
parent compound, leads to Long Q-T interval, possible death.
CYP3A4 metabolizes wide range of drugs
Substrates don’t necessarily have similar structure
Drugs affect the pharmacokinetics of each other.
Many over-the-counter medications have agents that inhibit the metabolism of other drugs.
E.g. Cimetidine (Gaviscon) inhibits metabolism of other drugs by inhibiting CYP3A4
“Metabolic bottleneck”: too many compounds compete for same enzyme. Limited active
sites; competitive inhibition.
Grapefruit: agent inhibits metabolism of other drugs via CYP3A4
Knowing which enzymes metabolize a particular drug is important for
Basic scientists mechanism of metabolism
Pharma drug development
Regulatory agencies that license drug
physicians, patients who wish to avoid drug-drug interactions
There are a wide variety of technologies that predict which enzymes are involved with the
metabolism of drugs.
“in silico” (computer modeling) predicts CYPs by comparing structure of active
sites.
1. Infer how metabolism proceeds in animals/animal tissues of known enzyme status
2. In vitro with enzymes purified from human tissues
Animals in which genes for specific DMEs have been knocked out are informative
about pathways of biotransformation of compounds. (Help predict enzymes involved)
3. In vitro with enzymes cloned, expressed as “reagents”
BUT: products of orthologous (similar) genes do not equate to identical; function
across species.
e.g. Mouse CYPs do not have identical catalytic functions of that of human orthologs
(may not have same substrate selectivity)
Reaction phenotyping kits identify CYPs responsible for metabolism of xenobiotics.
Kit contains individual and pooled human liver microsomal samples
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