Pharmacokinetics: Drug Metabolism Flashcards
Why would you want a drug to be lipophilic?
So drugs can access tissues – therapeutic effect
Why would you want a drug to be water soluble?
Retained in the blood and delivered to excretion sites
If a drug is water soluble it is less likely to access the tissues and thus is easier to excrete.
Describe the bi-directional movement of drugs
Each drug entering a tissue may leave it again- just physics- depends on concentration gradients which direction the NET movement will be
What is important to remember about the movement of lipid soluble and water soluble drugs
Some lipid soluble drugs will be excreted (won’t pass through barriers)
Some water soluble drugs will enter the tissues and pass through the barriers.
Summarise what body does to drugs in its metabolism
We design relatively lipid soluble drugs.
Body alters the drug to make it less lipid soluble and easier to excrete.
The process of metabolism involves the conversion of drugs (usually quite lipid soluble) to metabolites (usually less lipid soluble and easier to excrete).
Summarise metabolic transformation
§ Xenobiotics (drugs/foreign compounds) are usually lipophilic.
§ Metabolism tends to reduce or eliminate pharmacological activity.
§ Metabolism converts lipophilic chemicals to polar derivatives (which are readily excreted).
Summarise the two phases of drug metabolism
Drug metabolism involves two kinds of biochemical reaction
Phase 1 – main aim is to introduce a reactive group to the drug (increase polarity)
Phase 2 – main aim is to add a water soluble conjugate to the reactive group
Describe first phase reactions
Phase 1 reactions (oxidation, reduction or hydrolysis) are catabolic, and the products are often more chemically reactive and hence, paradoxically are more toxic or carcinogenic than the parent drug. Phase 1 reactions often introduce a reactive group, such as hydroxyl, into the molecule, a process known as ‘functionalisation’. This group then serves as a point of attachment for the conjugating system (phase 2) to attach a substituent such as a glucuronide.
Where are the microsomal enzymes that take place in phase 1 reactions found
In the SER of hepatocytes. They are called microsomal enzymes because, on homogenisation and differential centrifugation, the ER is broken into very small fragments that sediment only after prolonged high speed centrifugation in the microsomal fraction. To access these enzymes in life, a drug must cross the plasma membrane.
What is the result of the different phase 1 reactions
Oxidation/reduction creates
new functional groups
Hydrolysis unmasks them.
Important – functional group
serves as a point of attachment
for phase II reactions
What will phase 1 oxidation reactions produce
Electrophiles:
R=O
R-R ( each R joining to an O)
What will phase 1 reduction and hydrolysis reactions
Nucleophiles
R-OH
R-SH
R-NH2
What is the most common reaction in phase 1 metabolism
Most common Phase 1 metabolism = oxidation (often start with hydroxylation and then oxidise that compound)
Summarise the cytochrome P450 enzymes
S.E.R.
57 enzymes
Different subsets- metabolise different drugs
We all have different variations of these enzymes
Precision medicine- hard to predict how each patient will respond to each drug
What is aspirin oxidised to
Salicylic acid
What are the 3 scenarios in phase 1 metabolism
Active parent drug Inert metabolite
Examples are cocaine and nicotine
Active parent drug Active metabolite
(prolongs effects)
Examples is cannabis, delta-9-tetrahydrocannibol is the active parent drug, but 11-hydroxyl THC is one of the metabolites and is more powerful- complicates things massively- will only monitor active parent- but metabolite is also active and will produce effects
Inactive parent drug Active metabolite
(prodrug)
Codeine is an example of this- needs to be metabolised to morphine first.
Summarise phase 2 metabolism
§ The conjugate is almost always pharmacologically inactive.
§ The reaction creates molecules that are less lipid soluble and easier to excrete (as they aren’t reabsorbed in the tubules of the kidneys). Conjugating agent = an agent that attaches a polar group onto the molecule in question.
What is the conjugating agent for the electrophiles
Glutathione-
What are the different conjugating agents for nucleophiles
UDP-glucuronic acid — -OH, -COOH, -NH2, -SH
Acetyl coA —- -OH, -NH2
3-phosphoadenosine, 5-phosphosulfate —- -OH, -NH2
Hence the 3 reactions are:
Glucuronidation
Acetylation
Sulfation
Describe Glucuronidation of aspirin
Glucuronidation is low affinity/high capacity – more likely to occur at high drug dosages.
High capacity means lots will be metabolised in this way
Describe the sulfation reaction of paracetamol
Sulfation is high affinity/low capacity – more likely to occur at low drug dosages.
40-60% metabolism
Describe the reaction of paracetamol with UDP-glucuronic acid
Low affinity/high capacity
20-30% metabolism
What is required to biotransform a drug into an electrophilic conjugate
Drug needs to be electrophilic to be conjugated or biotransformed to an
electrophilic conjugate.
How can we convert paracetamol to an electrophile
(clue – oxidation can mean gaining oxygen OR losing
hydrogen)
Remove a hydrogen atom from the nitrogen to form NAPQI (phase 1 metabolite).
This can then be conjugated by glutathione
What is the issue with the metabolism of paracetamol into NAPQI
NAPQI is an electrophile- which is extremely reactive
During a paracetamol overdose- the glutathione system can become overwhelmed and can’t metabolise NAPQI as quickly, leaving NAPQI free to cause liver damage by reacting with proteins in the liver causing massive liver dysfunction
What are the 3 other phase 2 metabolic reactions that are less common
Other Phase 2 metabolism pathways = acetylation, methylation, amino acid conjugation
Less common than previous 3
Describe acetylation
§ The acetyl group is transferred to an electron rich atom. Acetyl-CoA is the conjugating agent.
coA SH also formed
Acetyl coA is the donor
Donated to an electron rich atom (N,O or S)
N-acetyltransferase is the enzyme
R usually an aromatic amine
Isoniazid is metabolised in this way
Describe methylation
§ A methyl group is added to the electron rich atom. S-adenosyl methionine is the conjugating agent.
S-adenosylhomocysteine is also formed
H3C-O-R is produced
Targets R-OH, R-NH2, R-SH, R-NH-R
METHYLTRANSFERASE IS THE ENZYME
Levodopa is metabolised in this way
Describe amino acid conjugation
Two reactions possible
with carboxyl group of amino acid
with amino group of amino acid
Describe the amino acid conjugation using the carboxyl group
Acetyl coA is conjugated using acyl-coA synthesase, the coA-SH group is then removed using acyl coA amino acid N acyltransferase
ATP hydrolysed to AMP in first step
Describe the amino acid conjugation using the amine group
Serine added and ATP hydrolysis- converted to intermediate using seryl- tRNA synthesase
Serine added to this intermediate to make the reactive nitrenium ion
Describe the importance of drug metabolism
The biological half-life of the chemical is decreased.
The duration of exposure is reduced.
Accumulation of the compound in the body is avoided.
Potency/duration of the biological activity of the chemical can be altered.
The pharmacology/ toxicology of the drug can be governed by its metabolism.
What is common about the intermediates
§ …involve high energy intermediates such as UDPGA for glucuronidation or PAPS for sulphation.
Summarise sulfation
§ Sulphotranferases catalyse transfer of sulphate to substrates. 3’-phosphoadenosine-5’-phosphosulphate is the conjugating agent.
Summarise glucuronidation
§ Drug-OH + UDPGA à Drug-O-D-glucuronide.
§ A high energy phosphate compound is created. UDP-glucuronic acid is the conjugating agen
What do the effects of cannabis last longer
Both the active parent and metabolite are active and lipid soluble- prolonging its effects- can diffuse into fats and remain as a reservoir in the fats- diffuse back into blood- really complex
