Drug Metabolism Flashcards
Why must metabolism be accounted for when determining dosage regimen?
Drug will be eliminated, so important to account for this to have therapeutic concentrations in the blood
Importance of drug metabolism in the body?
a dominant elimination route for many therapeutic drugs
Purpose of drug metabolism?
- alters physchem properties of the molecule (easier elimination)
- prevents drug accumulation
What is the most common cause of DDIs?
Inhibition of metabolic enzymes in the liver/intestine, which leads to reduced metabolism of drugs. severe DDIs lead to safety issues and even withdrawal from market
Characteristics of drug metabolising enzymes?
- very broad substrate specificity
(drugs, environmental chemicals, dietary chemicals, endogenous compounds) - predominantly located in the liver but also found in he intestine and kidney
- ubiquitious - present in all animal species (original purpose was to protect from phytochemicals in diet). exposure is not more extensive via a wide range of drugs
What physicochemical changes can be made by metabolic enzymes to molecules?
Metabolites may be:
- less lipophilic
- more water soluble
- pKa to stronger acids etc
- better renally cleared
than the parent drug. purpose for much easier renal elimination
Pharmacological properties of metabolites?
- metabolites usually don’t have a therapeutic effect (though there are a few exceptions, e.g. ezetimibe glucuronide)
- metabolites aren’t generally toxic
- sometimes plasma conc of metabolites can be greater than that of the parent drug
- some metabolites inhibit metabolic enzymes/transporters - can contribute to DDIs
Role of the liver in drug metabolism/elimination?
- most importnat due to size, blood flow and high enzyme levels
- some drugs are eliminated unchanged via biliary excretion e.g. pravastatin
- anatomical position - extensive first pass
- infrastructure and subcellular localisation of enzymes
What are the phases of enzymes (+ examples) in the liver?
- Phase 1 - CYP450 enzymes
- Phase 2 - e.g. UGT - glucuronidation
Where in the cells are most oxidation enzymes located?
Membrane bound so in the microsomes
- microsomes obtained through homogenisation and centrfugation
Uses of microsomes for in vitro studies?
Human microsomes from liver, intestine and kidney are widely used in drug development. can investigate metabolic possibility in those organs
Alternatives to microsomes for in vitro studies?
recombinant proteins (just one enzymes instead of all of them)
whole hepatocytes
chips
What are the different drug metabolism reactions - phase 1 and 2
- oxidation
- reduction
- hydrolysis (phase 1 ^)
- conjugation (phase 2)
Which of the drug metabolism reactions is the most significant?
oxidation
Which enzyme family catalyses oxidation reactions?
Cytochrome P450 - superfamily
What is the difference in metabolism mechanisms with many new drugs?
Immediately metabolised by conjugation (‘phase 2’)
General principles of Phase 1 reactions
introduce or expose functional groups
At which groups do oxidation reactions occur?
C, N or S
C - hydroxylations, aromatic or aliphatic
N and S oxidation
N- O- or S- dealkylation
At which groups do reduction reactions occur?
Nitro or keto groups
At which groups to hydrolysis reactions occur?
Amide or ester
What are the three different types of oxidation reactions?
aromatic, aliphatic, de-alkylation
What are the two mechanisms for oxidation reactions?
hydroxylation and cleavage
What does aromatic oxidation result in?
Phenols
What does aliphatic oxidation result in?
Alcohols
can occur on both the main chain and side chains
What does O-dealkylation result in?
phenols/alcohols
What does N-dealkylation result in?
Amines
What other oxidative cleavage reactions are there?
deamination
desulphuration
dechlorination
What does nitro group reduction result in?
Amines
What contributes to nitro group reduction and what are the consequences of this?
Liver enzymes and gut flora
Gut flora can vary massively so leads to interpatient variability in metabolism
What does Azo group reduction result in?
Amines
What does keto group reduction result in?
Secondary alcohols
What enzymes catalyse hydrolysis?
Carboxylesterases
What can happen in sequential metabolism?
- Phase 2 reactions (conjugation)
- Further phase 1 reactions e.g. sequential oxidation on the same carbon (alcohol -> COOH)
- or: sequential oxidation on a different e.g. hydroxylation of a demethylated metabolite
What is parallel metabolism?
Competing metabolic reactions that occur to the parent molecule (not sequential, just different pathways the parent drug can go down)
Points to use to predict the routes of drug metabolism
Any key functional groups - -OH, -NH2 or -COOH, may be susceptible to direct phase 2 metabolism (conjugation)
Other vulnerable groups - Esters, nitro, O-methyl etc
N or O present? Oxidative cleavage
Any other C groups vulnerable to oxidation (e.g. aromatic oxidation)
Where in the molecule are reactions most likely to occur?
The alpha carbon - next to an electronegative moleucle e.g. O or N (or C=C)
- N-C-R
- O-C-R
- C=C-C=R
also consider side chain hydroxylations and aromatic hydroxylations
What in vivo methods can be used to identify metabolites and start building up metabolic pathways for drugs in development?
- Products in excreted urine (mainly terminal metabolites)
- Products circulating in plasma
What in vitro methods can be used to identify metabolites and start building up metabolic pathways for drugs in development?
- Products formed in incubations with liver tissue (e.g. liver microsomes)
Why is complete recovery of metabolites difficult?
Some metabolites are unstable or non-recoverable
