Drug Metabolism Flashcards by Ambra Copping

What are the two types of metabolism?

Phase I
Phase II

How well did you know this?

Not at all

Perfectly

What is phase I metabolism?

Functionalisation reaction
Produces or uncovers a chemically reactive functional group
It prepares the drug for phase II

How well did you know this?

Not at all

Perfectly

What is phase II metabolism?

Conjugation reactions
Conjugation of functional group with less reactive species
Phase II reactions represent a detoxification step and generate compounds that are inactive and readily excreted

How well did you know this?

Not at all

Perfectly

What are the features of cytochrome p450 enzymes?

Oxidise anything
Membrane bound monooxygenase in the sER
An enzyme which is not specific and can metabolise more than 120 different drugs

How well did you know this?

Not at all

Perfectly

Describe the cytochrome p450 enzyme:

Has a large lipophilic space that molecules can enter into in a range of different orientations
At the bottom there is a redox reactive haem group, the reduce active ion

How well did you know this?

Not at all

Perfectly

How is CYP450 produced?

Needs a co-factor of cytochrome reductase
NADPH binds to the NADPH-binding domain of P450 reductase and electrons are shuttled from NADPH through FAD and FMN to the P450 heme.

How well did you know this?

Not at all

Perfectly

What are the two most common CYP450 phase conversions?

Hydroxylation and Dealkylation

How well did you know this?

Not at all

Perfectly

Describe hydroxylation in a CYP450 phase conversions:

Addition of an oxygen into the subsrate
The highly reactive Fe(V) species abstracts a proton from the substrate to give the carbon centred radical R. attached to the Fe(IV)-OH species
This radical then pulls the OH from the Fe4+ followed by release of the product and regeneration of Fe3+.

How well did you know this?

Not at all

Perfectly

Describe dealkylation in a CYP450 phase conversions:

Whenever hydroxylation occurs α to a heteroatom you will get a dealkylation reaction because a “hemiacetal type” intermediate will be formed.

How well did you know this?

Not at all

Perfectly

What are the conditions in which a dealkylation in a CYP450 phase conversion happens?

Occurs to the carbon next to the X
X= O,N, S or P
Has to be atleast one hydrogen on the carbon as needs to be extraction on the hydrogen

How well did you know this?

Not at all

Perfectly

Name 5 other important phase I conversions using CYP450:

Dehydrogenation to give alkenes
Epoxidation of alkenes
Epoxidation of aromatic rings
Dihydroxylation of aromatic rings
Hydroxylation of aromatic rings

How well did you know this?

Not at all

Perfectly

Name 4 important phase I conversions not using CYP450:

Hydrolytic enzymes
Epoxide hydrolase
Ethanol metabolism
Other oxidases

How well did you know this?

Not at all

Perfectly

Describe how hydrolytic enzymes are involved in non- CYP450 phase I conversions:

Carboxylesterases hydrolyse esters and some amides
Amides are more stable than esters
The more lipophilic the amide, the better the substrate

How well did you know this?

Not at all

Perfectly

Describe what are epoxies?

Often generated by CYP450 activity
Electrophillic and alkalate
Very reactive with DNA and proteins
-polycylic aromatic hydrocarbons
-Aflatoxin B1
Usually carcinogenic

How well did you know this?

Not at all

Perfectly

How do epoxies cause cancer?

Covalently bound epoxide to nitrogen on DNA so breaks purine base
Leads to apurinic DNA so strands break and mutate

How well did you know this?

Not at all

Perfectly

How is ethanol metabolised?

Ethanol is metabolised to ethanal using alcohol dehydrogenase and NAD+
Ethanal is then converted into ethanoic acid using aldehyde dehydrogenase and NAD+
These dehydrogenase are oxidation reactions

How well did you know this?

Not at all

Perfectly

Why is the rate of ethanol metabolism limited?

Large amounts of NAD+ cofactor are needed for metabolism
2 moles of ethanol requires 1.5 Kg
Rate of ethanol metabolism limited to 8g/h in most adults

How well did you know this?

Not at all

Perfectly

What symptoms can ethanol cause and why?

Ethanol is converted into ethanal
Large amounts of circulating ethanal is the factor contributing to:
-Flushing
- Tachycardia
- Hyperventilation
- Panic/distress
Ethanal can leak into the system in high concentration and have toxic side effects

How well did you know this?

Not at all

Perfectly

What drugs are used in ethanol aversion therapy and how do they work?

Study These Flashcards

Disulfiram
Used to inhibit aldehyde dehydrogenase so elevated levels of ethanal in the blood, which causes extremely unpleasant side effects but isn’t harmful

What other drugs react in a similar way as ethanol aversion therapy?

Study These Flashcards

Chlorpropamide
Nitrofurantoin
Metronidazole

What is the consequence of chronic alcohol consumption?

Study These Flashcards

Results in induction of CYP2E1 activity
CYP2E1 metabolises alcohol and other drugs:
-Warfarin
-Paracetamol
-Phenobarbital
So may need higher doses as lower doses not as effective

What are non-CYP450 phase II reactions for?

Study These Flashcards

Prepare functionally activated compounds for excretion in the bile or urine
Conjugation of xenobiotic with one of a variety of different compounds
Results in a pharmacologically inactive soluble compound

What are the main reaction types of non-CYP450 phase II reactions and the enzyme used?

Study These Flashcards

*Glucuronidation- UDP- Glucuronyltransferase
*Methylation- Methyltransferase
*Glutathione conjugation- Glutathione-S- transferase
*Sulphation

What is Glucuronidation?

Study These Flashcards

Most widespread form of conjugation
Conjugation with sugar, glucuronic acid (liver is a rich source of this)
Glucuronic acid transferred from high energy phosphate compound UDP-GA to electron rich atom (N, O or S)

What it UGT?

Involved in Glucuronidation UDP-glucuronosyl transferase enzymes Located in the endoplasmic reticulum of the liver

What is sulphate conjugation ?

Involves the addition of SO3- to drug Major conjugation pathway for phenols and can occur for alcohols, amines and occasionally thiols Requires energy rich donor compound Sulphate conjugation involves the interaction of drug with PAPS Metabolism involves the enzyme sulfotransferase- non specific

What is glutathione conjugation?

Tripeptide glutathione (GSH) contains Glu-Cys-Gly Many drugs are metabolised to toxic electrophiles and GSH is conjugated with these toxic electrophiles Includes epoxides, haloalkanes, nitroalkanes, alkenes, aromatic halo- & nitro-compounds

What is GST and what is it used for?

Glutathione S-transferase- where glutathione exists as a thiolate anion GST catalyses the nucleophilic addition of thiolate anion to electrophilic centres in xenobiotics Generates a less toxic compound that is modified to a mercapturic acid derivative that is excreted

How can glutathione be linked to cancer?

Overexpression of glutathione can be linked to resistance in cancer As N-mustards work by alkylating guanine residues in DNA and Glutathione deactivates the N-mustards as they cant reach the active site

How is the over expression of glutathione in cancer stopped?

Drugs sometimes given with buthione sulfoximine- an inhibitor of GST

What is the major route of paracetamol metabolism?

Phase II metabolism O-sulfate in children O-glucoronate in adults Then elimination

What is the minor route of paracetamol metabolism?

Phase I metabolism using CYP 2E1 Which produces a highly reactive Micheal acceptor N-acetyl iminoquinone

What can happen if you overdose on paracetamol?

N-acetylimidoquinone is either eliminated by glutathione It can also form hepatic proteins, when there is high levels of paracetamol, a depleted level of glutathione so has to form hepatic proteins (toxic metabolite) which leads to: -hepatic necrosis -renal failure -death

How would you treat a paracetamol overdose?

Treat with N-acetylcysteine (GSH precursor) within 12 hours

What is polymorphism?

Mutations that can change the gene sequence Polymorphism can result in amino acid changes that alter activity of the protein

What are the consequences of polymorphism?

Can cause an increase in protein activity (extensive metabolisers) Can cause decreased/absent protein activity (poor metabolisers) Altered substrate specificity of enzyme

What are SNIPS?

SNP- Single nucleotide polymorphism Represent the most extensive genetic difference between individuals

What is the polymorphism mutation that causes codeine to not be able to form morphine?

Variant of CYP2D6

What is CYP3A4?

Metabolises 50% of drugs Polymorphisms rare, unknown functional consequence

What is CYP2C9 and the polymorphism consequence?

Metabolises 20% of drugs; NSAIDs, warfarin, phenytoin 2 allelic variants are poor metabolisers

How can St Johns Wort interact with other drugs?

Increased levels of CYP3A4 CYP3A4 metabolises 50% of all prescription drugs

Name and describe how some drugs can inhibit CYP450 metabolism:

Competitive/non-competitive inhibition- chloramphenicol Metabolite of drug binds CYP450 and forms an inactive complex- Desipramine & Isoniazid Olefinic & Acetylinic drugs can cause CYP450 haem destruction- Secobarbital & Ethynylestradiol

How can a young age exhibit poor drug metabolism and give examples:

Virtually no phase 2 metabolism- Chloramphenicol toxicity due to poor glucuronidation Limited Phase 1 enzyme activity- CYP3 activity only

How can an old age exhibit poor drug metabolism and give examples:

Men and women >65-70 years significantly decreased drug metabolism Diminished enzyme induction

How can alcohol liver disease cause an impact on drug metabolism?

Prolonged exposure leads to inflammation and hepatocytes accumulating fat droplets Continued exposure results in fibrosis & cirrhosis

How can cirrhosis have an impact on drug metabolism?

Liver tissue replaced with fibrous tissue so a decrease number of functional hepatocytes Greatest impact on CYP450 dependent metabolism Little effect on glucuronidation dependent metabolism It can affect blood flow through liver

Name the amino acids which can be protonated at physiological pH:

Lysine (+ve) Arginine (+ve) Glutamic acid (-ve) Aspartic acid (-ve)

Drug Metabolism Flashcards

(47 cards)