Drug metabolism reactions - elimination Flashcards
What is elimination?
- Metabolism + excretion (2 mechanisms)
- It is the irreversible removal or loss of a drug from the body
Where does metabolism predominantly occur?
Liver and some in the intestine
What is the dominant mechanism of elimination?
metabolism
What happens during metabolism?
- Involves a chemical reaction - change in structure of molecule, changing functional groups and therefore properties
- Conversion to metabolites
What properties do metabolites have?
They are more polar and hydrophilic than the parent molecule, this prevents drug accumulation.
What is excretion?
Elimination of unchanged drug or its metabolites from the body
Where does excretion occur?
Mostly in the kidney - via urine, although can occur in the liver (biliary excretion via efflux transporters and into faeces) and in the lungs (pulmonary, for inhaled molecules)
Are metabolites that are formed generally active or inactive?
Generally inactive and LESS toxic than the parent molecule
What drugs show exceptions to the usually inactive metabolite?
Prodrugs - inactive or weakly active drug that produces active metabolite e.g. levodopa –> dopamine (conversion is necessary to form the active drug)
What is the most common cause of DDIs?
Inhibition of metabolic enzymes in the liver/intestine
What properties of metabolites facilitate elimination?
- Low lipophilicity
- high water solubility
- strong acids
Do metabolites have a therapeutic value?
No, they are not pharmacologically active.
However, there are some exceptions: ezetimibe glucuronide, morphine 6-glucuronide
What can some metabolites do that contributes to DDIs?
Inhibit metabolic enzymes and transporters (gemfibrozil glucuronide, itraconazole metabolites)
Why is the liver the most important for metabolism and elimination?
- Large in size
- Dual blood flow from portal vein and hepatic artery
- High enzyme concentration in hepatocytes
What do liver cells have high expression of?
Phase 1 enzymes (CYP450s) and phase 2 enzymes (e.g. UGT - glucuronidation)
What subcellular fractions in the liver are used for studying drug metabolism in vitro?
Enzymes placed in the membrane of the endoplasmic reticulum (broken up by homogenisation).
- they are centrifuged sequantially to give microsomes
Where are most oxidation enzymes found?
(CYP450s) are membrane bound and located in microsomes
What are the 4 drug metabolism reactions?
- Oxidation
- Reduction
- Hydrolysis
- Conjugation
- 1-3: phase 1 reactions
4: phase 2 reaction
What is the most important metabolic reaction?
Oxidation:
- catalysed by a super family of enzymes (CYP450s)
- many new developing drugs are metabolised by direct conjugation
Describe a common phase 1 reaction?
Parent molecule: undergoes an initial reaction (often oxidation) and a certain functional group is introduced - therefore changing the chemical structure of the molecule
Describe a phase 2 reaction?
Sequential metabolism (often conjugation reactions)
Where does oxidation occur on a molecule?
At C, N or S atoms
What are the 3 types of oxidation reactions?
o C hydroxylation: aromatic or aliphatic Cs
o Cleavage: loss of alkyl or amino group (N-,O-,S-dealkylation)
o N and S oxidations
Where does reduction occur?
Acts on nitro and keto groups
Where does hydrolysis occur?
Acts on ester and amide groups
What are the 3 oxidation reactions at carbon?
- Aromatic (hydoxylation)
- Aliphatic (hydroxylation)
- De-alkylation (oxidative cleavage)
*2 apparent different mechanisms: hydroxylation and oxidative cleavage
What does aromatic oxidation result in the formation of?
PHENOLS:
- addition of OH group to aromatic ring (hydroxylation)
What does aliphatic oxidation result in the formation of?
ALCOHOLS
What type of oxidation is de-alkylation?
Oxidative cleavage
What are the 2 types of de-alkylation?
a) O-dealkylation – results in formation of phenols – codeine (eliminate methyl group)
b) N-dealkylation – results in formation of amines (again, eliminate methyl groups)
What are other types of oxidative cleavage reactions?
o Deamination
o Desulphuration
o Dichlorination
(all involve initial carbon oxidation)
What contributes to reduction reactions?
Liver enzymes and gut microflora
What groups can be targeted to form a primary amine?
a) nitro group (NO2)
b) azo group (N=N)
c) keto group (C=O)*?
What are the 2 types of hydrolysis reactions?
Ester and amide hydrolysis
What are hydrolysis reactions catalysed by?
carboxylesterases (expressed in liver and intestine)
Where does sequential oxidation occur?
- Sequential oxidation on the same C (CH2OH–>COOH)
* Sequential oxidation on a different C (E.g. hydroxylation of a demethylated metabolite)
What is parallel metabolism?
- Competing reactions
- Can undergo phase 1 CYP450 reactions
- direct conjugation can also occur as well as direct sulphonation
- all happen in parallel
