Drug Metabolism Flashcards
Where does metabolic transformation occur?
primarily in the liver
What is Hepatic First Pass Metabolism?
metabolic conversion of the drug into something that is different before the drug enters the general circulation / the effect that occurs the very first time the drug passes through the liver
- If the metabolism is extensive you may only release a small amount of the active drug into the systemic circulation (low bioavailability)
- First pass metabolism can be pre-hepatic-intestines, stomach, oesophagus and buccal cavity have a small amount of metabolism capacity
- If a drug undergoes extensive first pass metabolism giving it a low bioavailability then an option is to give it intravenously(but this is invasive)
What are the types of metabolism?
Phase 1 - oxidation, reduction and hydrolysis
Phase 2 - glucuronidation, acetylation, sulfation, methylation, glutathion conjugation (adding polar side group so it’s soluble and can be excreted)
What happens in phase 1 metabolism?
All about releasing or making functional groups
•Oxidation/reduction creates new functional groups
•Hydrolysis unmasks functional groups
- These functional groups will serve as a point of attachment for phase II reactions •Phase I reactions often inactivate drugs but they can also activate drugs (prodrugs)
- With phase I reactions there is little change in polarity -you introduce a functional group but if the drug was lipophilic when it started then it’ll still be prettylipophilic
Describe the cytochrome P450 enzyme system
Phase I reactions primarily occur in the liver- the liver contains an enzyme system called cytochrome P450
•In humans there are 57 enzyme sinvolved in the cytochrome P450 system
- This is the main system involved in Phase I oxidising reactions
- It is involved in the metabolism of MOST drugs
- Cytochrome P450 enzymes are predominantly found in the LIVER
- P450 is also involved in the metabolism of endogenous compounds such as steroids and oestrogens
- There are several isozymes involved in drug metabolism
- Some drugs can inhibit or induce CYP450 -this is bad because you’re changing the ability of this system to handle certain drugs
RH (drug) + NADPH+O2+H+ -> ROH (oxidised drug)+NADP++H2O
drug binds to P450 -> at the centre of P450’s catalytic site there is catalytic iron and it is in the oxidised state (Fe3+)-> allP450 enzymes have a porphyrin ring and iron (Fe3+) at its active site -> drug binds to the iron in the catalytic site -> electron is donated by NADPH -> electron is then picked up by the P450 complex and you get reduction of Fe3+ –> Fe2+ -> molecular oxygen binds to the catalytic site so P450 now has Fe2+ and oxygen bound to it -> the Fe2+ loses an electron to become Fe3+ and nothing has happened to the drug but the oxygen picks up the extra electron and becomes unstable -> a second electron from NADPH is picked up by Fe3+ to become Fe2+ again - >Fe2+ donates this electron to oxygen (and hence becoming Fe3+) so the oxygen is very unstable(drug still hasn’t changed)-> conversion of the drug into the hydroxylated derivative and we lose the reactive oxygen as water by picking up two protons -> drug is released and the P450 returns to the cycle with iron in its oxidised state (Fe3+) ready to undergo the next cycle
•IMPORTANT: oxidation reactions involve a hydroxylation step catalysed by the P450 system
What is the effect of oxidation on aliphatic and aromatic drugs?
aliphatic - e/g pentobarbitone - hydroxylation removes pharmacological activity
aromatic - e.g acetanilide (pro drug for paracetamol) - hydroxylation -> paracetamol
What is n-demythylation? Give an example
oxidation of methyle group in a nitrogen environment (carbon on nitrogen)
imipramine -> formaldehyde
- 80-90% of drugs have amine functions in them
- This is a very effective way of removing pharmacological activit
What is O-demethylation?
Give an example
oxidative attack by P450 on a methyl group on an oxygen
This converts oxygen to the hydroxyl group and we release formaldehyde and generate morphine (from codeine)
What is n-oxidation?
oxidation of the nitrogen group itself
•This generates an amine oxide(oxide of atertiary amine)
•Nitrogen is trivalent so in its outer shell it has 2 lone electrons
•Normally, the nitrogen doesn’t use these electrons to make chemical bonds but in certain circumstances they can donate both these electron (generally to oxygen) to make a dative bond
This has a medical relevance -flavin containing monooxygenase deficiency:
Humans generate trimethylamine in their GI tract (product of protein metabolism)
Trimethylamine smells terrible
In the liver, flavin containing monooxygenase converts trimethylamine into trimethylamine N-oxide which is odourless and polar so it can be readily excreted in the urine A small subset of the population has defective flavin containing monooxygenase so they produce trimethylamine but they can’t metabolise and excrete it so they sweat and breathe it out (fish odour syndrome)
What happens in alcohol oxidation?
Alcohol is metabolised by alcohol dehydrogenase and this shows zero-order kinetics
Alcohol is metabolised into acetaldehyde and then to acetic acid which is then removed •Flavin containing monooxygenase and P450 enzymes are found in the endoplasmic reticulum-on the inner membrane
•Alcohol dehydrogenase is a soluble enzyme -it is a cytoplasmic enzyme
What happens in reduction ?
- Prontosil is split through reduction
- Two amines are formed
- These reactions are LESS COMMON than oxidative reactions and it occurs in specific parts of the body
- The GI tract is a low oxygen environment so under these conditions reduction can work effectively
- Most reductases are bacterial enzymes that are colonising our gut which is why these reactions tend to happen in the GI tract
What happens in hydrolysis?
Procainamide is a local anaesthetic and it is metabolised around the amine function to generate a carboxylic acidand an amine
•This is catalysed by hydrolysis enzymes:
oEsterases-hydrolysis of an ester
oAmidase-hydrolysis of an amide
Describe the conjugate that is formed during phase 2 metabolism?
almost always inactive
less lipid soluble
more polar
easier to excrete
What is at the active site of P450?
iron
What are conjugating agents?
usually large, polar, endogenous molecule (requires energy to make)
they target specific types of functional groups
