L6: drug metabolism part 3 Flashcards
age- geriatrics and neonates?
- Decline in renal function
– decreased excretion - Increase in body fat
– increase in drug deposition - Decrease in liver mass with age
– no decrease in P450 function - Decrease in liver blood flow with age
– 0.5-1.5% per year
– reduce O2 availability for P450 activity
– at 70 years up to 40% decline in hepatic blood flow
compared to 30 year old - Reduction in G.I.T blood flow
Age - neonates
* < 4 weeks in age
* 30-50% CYP activity of adult
* t1/2 drugs increased 10 fold
* Premature babies reduced renal clearance
* CYP developmental patterns
– foetal-specific isoforms, e.g. CYP3A7
* endobiotic metabolism
* CYP patterns similar to adults 2-6 months
* 24 hours following birth UGT1A1 activated by
bilirubin
– jaundice
* GSH conjugation better than adults
* Phase I and Phase II reach maturity at 2 – 3 years
Could drug netabolism be helpful to the drug designer.
pro-drugs?
A prodrug is an inactive or less active compound that gets converted into the active drug inside the body. This is often done to improve absorption, targeting, or solubility.
🔁 How Prodrugs Work (What you described):
1. Esterification (Common Strategy)
You chemically modify the drug by attaching an ester group.
This makes the drug more lipophilic (fat-loving), so it crosses cell membranes more easily, especially in the gut.
Once inside the body (or the cell), esterases (enzymes that break esters) cleave off the ester, releasing the active drug.
✅ Example: Enalapril (a prodrug of enalaprilat, an ACE inhibitor).
- Glucose Conjugation (Transport-Targeting Strategy)
Attach glucose or a glucose-like group to the drug.
The body mistakes it for glucose and uses glucose transporters to move it into cells.
Once inside, enzymes cleave off the glucose, releasing the active drug.
✅ This strategy can be useful in targeting cancer cells, which often have high glucose uptake.
L-DOPA?
an anti-parkinsonin drug
Parkison disease- caused by loss of dopamine.
Give l-dopa taken up by aa transporter
Get decarboxylated to form dopamine
Examples
* Enalapril (ACE inhibitor)
– Oral availability
* Dipivefrin (glaucoma)
– Corneal permeation
* Xeloda (anti-cancer agent)
– Reduced toxicity and high tumour selectivity
hard vs soft drugs?
Hard” Drugs
* Compounds that contain structural characteristics
required for activity but are not susceptible to
metabolism
* Increased efficacy by avoiding metabolism
– No toxic metabolites are formed
* Unlikely to result in drug-drug interactions
– Lower dose can be administered, thus reducing
potential for toxicity
– However, less readily eliminated due to lack of
metabolism
– Not many examples of hard drugs
* Lisinopril (ACE inhibitor)
“Soft” drugs
* The opposite of pro-drugs, these compounds are
designed and synthesized as active compounds
which readily undergo metabolic inactivation
– Removal of pharmacological effect
– Can produce highly-reactive intermediates
* Many of which are toxic
– Variations in drug metabolism amongst people can
give rise to variations in drug response and toxicity
* Example: remifentanil (μ opiod agonist);
atracurium (muscle relaxant)
Do microdosing to get around problem: lhighly metabolised so toxic
immplications of metabolism for drug development?
Implications for drug development
* What enzymes are involved in key metabolic
pathways?
* Does clearance depend solely upon a single rate-
limiting enzyme?
* Is that enzyme subject to genetic or environmental
variation in activity?
* Are there any significant potentials for drug-drug
and drug-diet interactions?
* If yes, does development continue?
* If yes, what restrictions may have to be put in
place?
paracetamol toxicity?
look at these studies im so tired
