Drug metabolism Flashcards
what does metabolism refer to?
the enzyme - mediated biotransformation that alter the pharmacological activity of both endogenous and exogenous compounds
what does bio transformations increase?
hydrophilic character and to render metabolites water soluble which aids urinary excretion
what happens to hydrophilic molecules?
are dissolved in water and do not cross lipid membranes - retained in the renal nephron filtrate and excreted
what happens to hydrophobic molecules?
tend to be lipophillic and will cross lipid membranes - reabsorbed from the nephrotic filtrate back into circulation
how can hydrophilicity be increased?
adding a polar group
removing a non-polar group
how does biotransformation alter the activity of the drug?
can produce a pharmacologically inactive metabolite if there is a big disruption in the pharmacophore
or make the drug more active/less active/ toxic
what is an example of a biotransformation making a drug more active
removing an alkyl group from an oxygen in codeine to form morphine (O-dealkylation)
what does it mean if someone isn’t able to metabolise codeine into morphine?
they have a mutation of the enzyme
what’s an example of the metabolite being less active?
oxidative N-dealkylation of propranolol to nor-propranolol (alkyl group removed from nitrogen) - pharmacophore remains intact so still has some activity
what’s an example of a metabolite being toxic?
racemisation of R-thalidomide to S-thalidomide by isomerases (enantiomer conversion)
what happens during phase one reaction?
- converts parent compound into a more hydrophilic metabolite by adding or unmasking functional groups
- may be sufficiently polar to be readily secreted
what happens during phase II reactions?
- conjugation with endogenous substrate to further increase aqueous solubility
- glucuronide, sulphate, amino acid, peptide (glutathione)
- phase I usually precede phase ii reactions
where does most metabolism occur?
liver
what are the two types of oxidation reactions?
- oxygen is incorporated into drug molecule (hydroxylation)
- oxidation causes loss of part of the molecule (eg. oxidative deamination, N-de alkylation, O-dealkylation)
what is the structure of cytochrome P450?
- hemoprotein containing an iron atom which can alternate between ferrous(++) and ferric (+++) states held by porphyrin
- electron acceptor
how does metabolism of CYP450 occur?
drug enters the binding site
haem co-factor responsible for transferring oxygen onto the molecule
need different informs as one enzyme cannot recognise all drugs
how does aromatic hydroxylation occur?
take hydrogen off the aromatic group and puts it onto an oxygen to form a hydroxyl group
how does aliphatic hydroxylation occur?
hydrogen from alkyl group gets removed and placed back on with an oxygen to form a hydroxyl group
how does O-dealkylation of ethers occur?
takes the hydrogen off the drug and puts it on to the P450 oxygen to form a hydroxide and then transferred back to the substrate
- because there is two oxygens beside each other it becomes unstable so the alkyl breaks off and is removed as an aldehyde
how does N-dealkylation of amines occur?
takes off hydrogen from carbon (forming a reactive carbon), the oxygen from P450 adds onto the carbon but since it’s next to NH it will break off
what is the name of N-dealkylation of amines metabolites?
nor-metabolites
what can dealkylation generate metabolites called?
often called desalkyl metabolites
What is oxidation reactions not catalysed by cytochrome P450?
Flavin containing monoxygenase system
- present in liver but some is present in gut and lung (SER)
- oxidises nitrogen, sulfur and phosphorus hereoatoms directly
- used molecular oxygen, NADH, NADPH and FAD as co-factors
Alcohol dehydrogenase (can oxidise to their corresponding aldehydes and ketones respectively)
how does hydrolysis of cocaine occur?
by esterases
