ADME Three Flashcards
What is the most important site of drug metabolism?
The Liver
What places in the body can drug metabolism occur?
Liver
GI tract- bacteria and proteases
Intestinal walls- CYPs
Plasma- esterases (i.e breaks down acetylsalicylsate-aspirin)
What does drug metabolism result in?
Drug is converted by metabolising enzymes into water soluble metabolite
Why do metabolic enzymes convert drugs into water soluble metabolite?
Water soluble metabolite is:
- less likely to diffuse into cells and reach receptors (relies on passive diffusion to do this)
- Favours increased excretion in urine or bile(very large mw weight)
- Usually abolishes activity and terminates drug action
What are the exceptions to metabolite enzymes that breakdown drugs but dont deactivate them?
- Can promote activity i.e prodrugs: acetylsalicylate
- No change in activity: diazepam into nordiazepam
- Produces toxic metabolites (paracetamol-only if too much)
How many phases of drug metabolism are there?
Up to two
What is phase 1 of drug metabolism?
Addition or uncovering of a reactive group
i.e
Oxidation
Reduction
Hydrolysis
Makes molecules more susceptible to phase two reactions
What is phase two?
Conjugation of endogenous molecule with drug
i.e
Glucurnoide
Sulphate
Glutathione
Makes the molecule more polar, ideal for substrates in active transport and excretion (more water soluble)
What is the most important reaction for phase one metabolism?
Oxidation is the most important reaction for phase one metabolism of all drugs
What are the most important enzymes for the oxidation reactions?
CYPs = cytochrome P450 mixed function oxidase systems
Of the CYPs which are the most involved?
CYP1, CYP2 and CYP3
What does the oxidation reaction require?
O2, NADPH and cytochrome P450 reductase- huge range of substrates
This also oxidases a range of endogenous compounds.
Drug+ O2+H+ + NADPH forms Oxidised drug+H2O+NADP+
Whats an example of phase one action?
Phenytoin: (lipophylic)
Phase one: Hydroxylation, (OH forms) becomes slightly water soluble but INACTIVE now
Phase two: Conujugation by UDP glucuronosyl transferase (addition of Uridine Diphosphate Glucuronide)
Now is inactive and very water soluble.
So what metabolic processes can a drug directly undertake?
Phase one: can be excreted sometimes, otherwsie followed by phase two then excretion
Or
Straight to phase two and excretion (formation of a drug conjugate.)
What are the two methods of excretion?
Bile excretion (faecal excretion) Renal excretion (urine)
What are the factors influencing drug metabolism?
Mainly: The patients genetic constitution
Also: Organ function Diseases +other drugs Diet+cigarettes+alcohol age+sex+pregnancy
How many people dont respond to a drug?
1 in 5
How many people have a toxic response to a drug?
20-30%
How many people actually respond to the drug in the intended way?
50-60%
Whats an example of a drug that neonates have reduced metabolism for?
Theophylline, as they get older the half life decreases
As people age how does their body clearance change?
Drug Clearance ability decreases with age, but not too clinically relevant
Using theophylline what is the half life in several population categories?
Neonates = 30-60hrs
Children = 2-4hrs
Adults (non-smokers) = 6-10hrs
Adults (smokers) = 4-6hrs
Do get the same effect the drug maintenance dose must vary between populations
What happens to enzymes once exposed to an inducing agent?
When exposed to an inducing agent, enzyme synthesis initiated within 24hr of exposure, increasing over 3-5days.
This inducing effect causes increased enzymes that results in the removal of dug from a system faster
Once inducing agent is discontinued what happens to the induction effect?
Effect decreases over 1-3 weeks after inducing agent is discontinued.
What environmental factors lead to the inducing effect?
Smoking
Eating BBQ meat
Ethanol
Barbiturates
Rifampicin
What happens when drug metabolism is inhibited?
Rapid onset within 1 day
Exaggerated response with increased risk of toxicity
What are some examples of reversible inhibitors of drug metabolism?
Grapefruit juice
Lead (complex with CYP)
The induction of enzymes control what?
The induction of enzymes in the gut wall and liver determine the amount of drug that makes it into the blood stream from administration (bioavailibility)
