Drug Metabolism Flashcards
What does metabolism tend to do to a drug?
Metabolism tends to eliminate or reduce the pharmacological and toxicological activity of a drug
- Metabolism changes the drug structure usually in a way which means that it can no longer generate an effect on its target tissue
It makes the drug more polar and soluble so that it can more easily be excreted
- Reduces half life of the drug - i.e. reduces the amount of time the drug remains in the body
- Making it water soluble makes it more easier to excrete so once in the urine it does not cross the lipid bilayer of the tubules and enter back into the circulation
What is first pass metabolism?
Metabolic conversion of the drug into something that is different before the drug enters the circulation
This is relevant for when the drug is taken orally (major route of intake)
- The drug enters: GI tract → hepatic portal vein → liver → systemic circulation → liver (via hepatic artery)
- Before the drug enters the systemic circulation, it passes through the GI tract and liver
- These contain enzymes which can metabolically convert the drug, in most cases into an inactive form
- Therefore, it reduces the concentration of active drug entering the systemic circulation (reduced bioavaliability)
- Most of the metabolism is HEPATIC - i.e. takes place in the liver
- However, some metabolism can also be pre-hepatic - i.e. enzymes present in intestines (from gut microbiome and actual intestinal enzymes), or stomach
NOTE:
- First pass metabolism differs from drug to drug
- Not all drugs are converted to an inactive form - some metabolites can be active
- The proportion of the drug that is metabolised is dependent on:
- which enzymes are present in the body (not all enzymes will be relevant for metabolising a particular drug)
- concentration of the relevant enzymes in the body (and concentration of drug/substrate)
- there might be other factors affecting rate of enzyme activity for the relevant enzymes (e.g. pH)
What effect does extensive first pass metabolism have on bioavailability?
Extensive first pass metabolism DECREASES bioavailability of the drug
- Does this by converting a proportion of the drug into an inactive form
- Therefore, it reduces the proportion of active drug entering the systemic circulation
REMEMBER: this is only valid when the active drug is metabolically converted to an inactive metabolite - happens in most cases
How can you avoid first pass metabolism?
By giving a drug intravenously
What is the purpose of Phase 1 metabolism?
- Its main aim is to introduce a reactive/functonal group to the drug
- This group can then be used as a point of attachment in in phase 2 reactions (conjugation)
NOTE: Sometimes, phase 2 reactions can occur without phase 1 reactions occuring (not always as as straightforward as phase 1 then phase 2)
What are the 3 different conversions that can happen in phase 1 metabolism?
Active parent drug → inactive metabolite
- Most common with oral drugs in first pass metabolism leading to reduced bioavalability
- *Active parent drug → Active metabolite
- This prolongs the effect of the drug
Inactive parent drug (i.e. pro-drug) → Active metabolite
What are the three types of reaction that fall under phase I reactions?
- Oxidation - creates new functional groups
- Reduction - creates new functional groups
- Hydrolysis - unmasks functional groups
How do phase 1 reactions affect polarity of the drug?
They have little effect on the polarity of a drug
What is the most common type of phase I metabolism reaction?
Oxidation (often starts with hyroxylation = addition of an -OH)
What enzyme system is extremely important to drug metabolism? Where are these enzymes found?
Cytochrome P450
- Family of 57 enzymes
- Mainly found in the liver (in SER) and
- Capable of metabolising loads of xenobiotics (foreign chemicals)
These enzymes are found in the SER
What is the principal role of cytochrome P450 enzymes? Name the co-substrate and co-enzyme needed.
Principal role - oxidation of chemicals
Co-substrate (i.e. reacts with the drugs) - molecular oxygen (O2)
Co-enzyme - NADPH
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
What is N-demethylation? What does this reaction produce?
This is the oxidation of a methyl group in a nitrogen environment (carbon on a nitrogen) It produces formaldehyde (HCHO)
What does N-demethylation do to a drug?
It is an effective way of removing the pharmacological activity of a drug
What is O-demethylation?
Oxidative attack of P450 on a methyl group attached to oxygen This converts oxygen to the hydroxyl group and release formaldehyde (HCHO)
What is N-oxidation? Describe the type of bond formed.
It is the oxidation of the nitrogen group itself Nitrogen has two free electrons that can form a dative bond with oxygen This generates an amino oxide
