Lecture 5 - Drug Metabolism Flashcards
Why are mechanisms for drug metabolism needed?
Drugs tend to be lipophilic which are not easily excreted. They must be metabolised so they become more polar and thus more water soluble, they are then more easily excreted in the kidneys. The metabolism and subsequent excretion tends to eliminate or reduce the pharmacological, and importantly, the toxicological activity of the drug.
What is the major site of drug metabolism in the body?
The liver
What is meant by “first pass metabolism”? What is this termed if it occurs in the liver?
Any alteration of the drug via metabolism before it enters the systemic circulation.
Becomes “hepatic first pass metabolism”.
Why is first pass metabolism important when producing a drug and what is the ideal amount of first pass metabolism?
If the drug is metabolised extensively before it can enter the systemic circulation, very little of the drug is now pharmacologically active.
The ideal amount would be none and can be almost attained with IV administration.
What does the term “Bioavailability” mean?
This constitutes the proportion of the drug administered that enters the systemic circulation and becomes “bioavailable” to the body.
e.g. low bioavailability = extensively metabolised before systemic entry and vice versa
What is the alternative administration method if a drug is extensively first pass metabolised?
Intravenous administration (only problem is it’s invasive)
What are the 3 Phase I metabolic reaction types and which is the most common?
Oxidation (most common)
Reduction
Hydrolysis
What are the 6 Phase II metabolic reaction types and which is the most common?
Glucuronidation (most common) Acetylation Amino acid conjugation Sulphonation Methylation Glutathione conjugation
What is the main aim of Phase I reactions and which do which?
To release or create new functional groups
e.g. oxidation/reduction creates new functional groups while hydrolysis unmasks functional groups
Is there large or little change in polarity with Phase I reactions and do they tend to inactivate or activate drugs?
Little change in polarity
Often inactivate but can also activate (prodrugs)
What is a prodrug and how does it become a pharmacologically active drug?
A prodrug is an inactive substance that requires metabolism in order to become pharmacologically active.
Metabolism of the prodrug in the liver converts it to something pharmacologically active and it enters systemic circulation.
What is the main site of Phase I reactions and what enzymes does this organ contain that mainly carry out these reactions?
Liver
Cytochrome P450 enzyme system - 57 enzyme system, variety allows for metabolism for huge number of xenobiotics
What other substances do the P450 enzymes metabolise in the body?
Endogenous substances such as steroids and oestrogens
What is the danger of drugs that can inhibit or induce CYP450 and some examples?
Changing the system’s ability to metabolism and process certain drugs
e.g. drinking grapefruit juice before taking TERFENADINE renders drug useless, careful what drugs taken with WARFARIN as can cause excess bleeding, PHENOBARBITAL reduces P450 100x
What is the general reaction equation of CYP450 mediated oxidation a drug and what is needed for the reaction?
RH + NADPH + O2 + H+ --> ROH + NADP+ + H2O (R is drug, ROH is oxidised drug) Needed: - drug - NADPH (reducing agent) - Molecular oxygen - Source of protons (H+)
CYP450 enzymes catalyse a hydroxylation step to begin the process of oxidation, what are the steps in the cycle of reactions involved in this? (draw on paper if poss)
1) Active site of CYP450 enzyme contains a catalytic heme iron centre (fe3+)
2) Substrate binds to this active site and induces a conformational change in the enzyme
3) Electron is then transferred from NADPH to the P450 reducing Fe3+ to Fe2+
4) Molecular oxygen binds to the P450 active site and picks up the electron thus oxidising the Fe2+ to Fe3+ and the O2 becoming unstable (O2-)
5) Another electron is donated by another molecule of NADPH reducing the Fe3+ to Fe2+ again
6) Electron is moved onto the O2- again oxidising the Fe2+ back to Fe3+ and creating agitated O2(2-). Drug has still not changed by this point.
7) Agitated oxygen is then used to oxidise the drug to its hydroxylated derivative.
8) Oxidised drug detaches, the oxygen is cleaved from the enzyme and reacts with two protons to form water and P450 is recycled with its heme centre in the Fe3+ state.
What is the total number of different molecules required and released from one P450 oxidation cycle?
Required:
- Drug
- 2xNADPH
- O2
- P450
Released:
- Oxidised drug
- H2O
- P450
What are the 5 subtypes of metabolic Phase I OXIDATIVE reactions and explain what they are? Which of these are NOT catalysed by P450 enzymes?
- Hydroxylation (both aliphatic and aromatic), addition of OH group
- N-demethylation, removal of a methyl group attached to N atom usually replaced by H
- O-demethylation, removal of a methyl group attached to O atom usually replaced by H
- N-oxidation, addition of O to tertiary amine forming a dative bond from N to O (NOT P450 catalysed)
- Alcohol oxidation, alcohol (usually ethanol) converted to acetaldehyde then acetic acid which is removed (NOT P450 catalysed)
Why is N-demethylation a very common reaction and why is important regarding drug metabolism?
Very common due to 80-90% drugs having amine functional groups on them
Very effective way of REMOVING pharmacological activity
Which enzymes catalyse N-oxidation and alcohol oxidation reactions? (hint: it’s not P450)
N-oxidation = Flavin-containing monooxygenase
Alcohol oxidation = alcohol dehydrogenase
Reactions involving P450, flavin containing monooxygenase, and alcohol dehydrogenase are each which order reactions? (one of them is different)
P450 = first order
FC monooxygenase = first order
Alcohol dehydrogenase = ZERO order
Which enzymes are involved in reduction and hydrolysis (ester and amide) Phase I reactions?
Reduction - Mainly bacterial REDUCTASES in the GI tract
Hydrolysis - ESTERASES (for ester hydrolysis) and AMIDASES (for amide hydrolysis)
Are reduction and hydrolysis reactions more or less common than oxidative reactions and where do they occur?
Much less common
Occur in specific parts of the body e.g. the GI tract (low oxygen environment)
What are sometimes problematic products of Phase I reactions? (one of the reasons for Phase II reactions)
Can sometimes produce toxic metabolites
e.g. paracetamol metabolism
