PCL201H1 Lecture Notes - Lecture 12: Cytochrome P450, Fexofenadine, Metabolite

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P450 Inhibition
Terfenadine in Seldane
1985, pulled 1999
Metabolite fexofenadine is antihistamine
Terfenadine blocks hERG K+ channels in heart, QT prolongation, fatal arrhythmia
Erythromycin and ketoconazole inhibit CYP3A4 so terfenadine is active
One drug should inhibit metabolism of another drug because of broad specificity
Cimetidine also inhibits 3A4, narrow TI drugs should not be taken at same time of same
DME: metabolic bottleneck
Grapefruit inhibits 3A4
P450 Phenotyping
Which enzymes metabolism a particular drug
“in silico” methods cannot be used reliably
animal models of known enzymes may work: extrapolation is difficult
animal knockout genes: for specific DME: orthologous in animal not sam effect as in
In vitro: microsomes or cloned enzyme/POR
XenoTech approach
Pure enzyme from cDNA: Can do does not equal will do, need relevant concentrations,
pathways, variation, etc.
Correlation analysis from microsome bank: different levels of enzyme
Selective inhibition
Nabumetone converted to 6MNA
cDNA: 1A2 has built in metabolizing ability
Correlation: more 6 MNA with higher 1A2
Knockout: inhibit 1A2, less ability
Prefer NOT:
CYP3A4: metabolizes many drugs, many variations (induction, inhibition, drug-drug)
CYP2D6: polymorphic in genome (rapid/slow metabolizers)
Issues: which enzymes CAN metabolize, which enzymes and pathways are present, how well
do these enzymes work
Caffeine probe: assess 1A2 ability, test metabolites in urine for 1A2 metabolizing ability
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