Drug Metabolism Flashcards
What does metabolism tend to do to a drug?
- reduce the pharmacological and toxicological activity of a drug.
- more polar and soluble so that it can more easily be excreted.
What is hepatic first pass metabolism?
Metabolic conversion of the drug into something that is different before the drug enters the circulation.
In other words – the effect that occurs the very first time the drug passes through the liver.
Make the drug more water soluble to be excreted
What effect does extensive first pass metabolism have on bioavailability?
Extensive first pass metabolism -> low bioavailability
How can you avoid hepatic first pass metabolism?
Giving a drug intravenously
What are the three types of reaction that fall under phase I reactions?
Oxidation
Reduction
Hydrolysis
What is the purpose of Phase I metabolism?
It is meant to release or unmask functional groups that can be used in phase II reactions as a point of attachment
How do phase I reactions affect polarity of the drug?
They have little effect on the polarity of a drug
What enzyme system is extremely important to drug metabolism?
Cytochrome P450
What are the substrates and products of the Cytochrome P450 mediated oxidation reaction?
Substrates = drug, NADPH, oxygen (O2), protons (H+) Products = hydroxylated drug, NADP+, water
What do P450 enzymes have in their catalytic site?
They all have a porphyrin ring and an iron group (Fe3+)
Describe the oxidation cycle of Cytochrome P450.
The drug binds to the iron in the catalytic site of CYP450 An electron is fed in from NADPH, which is picked up by the Fe3+ making it Fe2+
Then molecular oxygen binds to the catalytic site and Fe2+ loses its electron to become Fe3+ again, and oxygen picks up the extra electronand becomes unstable
Then a second electron is donated by NADPH, which, again, reduces Fe3+ to Fe2+ Fe2+ then donates this electron to the already unstable oxygen to make it even less stable
Then we get conversion of the drug to the hydroxylated derivative and we lose reactive oxygen as water with the uptake of two protons
The drug is released and P450, along with its Fe3+, is ready to undergo another cycle
Where do reduction reactions tend to take place within the body and why?
GI tract because this is a low oxygen environment
Most reductases are bacterial enzymes that are colonising our gut, which is why these tend to happen in the GI tract
What effect do phase II reactions have on the drugs?
They make drugs more polar and water-soluble (less lipid-soluble) so that they can be excreted more easily
What are some features of conjugating agents?
Large
Polar
Endogenous
What is the most common type of phase II reaction?
Glucuronidation (addition of a sugar to a molecule)
