Induction And Inhibition Flashcards
What does Induction mean in relation to toxicology and metabolism
Induction refers to a specific drug-drug interaction that causes a drug/compound to cause a more rapid metabolism of another drug/compound in body
Why is Induction a concern when it comes to drug interactions in the body?
- Alter the efficacy of a therapeutic agent
- Alter the toxicity of drugs or environmental chemicals
Why are drugs with a narrow therapeutic index especially concerned with induction and inhibition?
Because they don’t have as much flexibility when it comes to the toxic and therapeutic range. Even a little bit outside of the index can be deadly
What are some strong drug-metabolizing inducers?
TCDD (Tetrachlorodibenzodioxin (environmental toxin)
Indocarbazole (found in cabbage family)
Benzopyrene (found in cigarette smoke)
What is special about benzo[a]pyrene for metabolism?
It can activate its own metabolism/bio transformation
Explain the bio transformation of TCDD from its entrance into the body and its metabolism journey
- TCDD enters the cytoplasm readily due to its lipophilic properties
- It will attach to a protein complex with accessory proteins
- Once attached it will move to the nucleus it will attach to ARNT, a protein involved in signaling AHR
- It can biotransform into CYP1A1, which is involved in lung cancer
Explain how Hyperforin, a compound present in ST. John’s Worts leads to a reduction in efficacy of hIV medication
Hyperforin is an active ingredient in ST. John’s Worts medication and when it is brought to the nucleus, it biotransforms into CYP3A4 which is a highly inducing enzyme that metabolizes HIV drugs
List a therapeutic benefit of induction of drug metabolism
In patients with neonate hyperbilirubin, the recommended treatment is phenobarbital because it increases the metabolism of bilirubin from the body by inducing UDR-gluronosyl transferase and elevating rate of glucorondiation (which is an enzyme process metabolizing bilirubin)
What benefit does induction of CYP1A2 in liver have for high risk breast cancer patients?
Oral does of indol-3-cardinal that induces CYP1A2 biotransforms into estrogen by inducing metabolism of 17 beta estradiol.
Why was Seldane pulled from the shelves.
It was pulled after some patients had died. Their deaths were due to Terfenadine in the drug being a cardiac poison and when it is not biotransformed into something less dangerous before entering the circulatory system, it will lead to arrhythmia death.
Terfenadine blocks cardiac/potassium channels prolonging QT interval on ECG.
How do pharma companies figure out which human enzymes will metabolize a particular drug?
The 3 step process is done via in vitro tests with human tissues.
- Pure enzyme expression
- Correlation analysis in human liver microsome bank from a bunch of donors
- Inhibition of selective enzymes with selective antibodies
Why wouldn’t pharma companies want CYP3A4 as the primary enzyme for drug metabolism
Because it already metabolizes many other drugs and high variability in humans and other drug interactions may inhibit or induce CYP3A4
Why wouldn’t pharma companies want CYP2D6 as the primary enzyme for drug metabolism?
High degree of genetic polymorphism which may lead to some individuals being rapid/slow metabolizers.
