Metabolism and Excretion Flashcards
(44 cards)
What is metabolism and excretion for?
body’s strategy for reducing exposure to potentially toxic compounds
What is xenobiotics?
chemicals foreign to body, limit bioavailibility of therapeutic drug
three main ways body protects itself?
prevent from entering blood or sensitive tissue (blood brain barrier)
physical removal from body (urine, bile, sweat)
biotransformation- products removed faster than parent compound
What is biotransformation?
increasing polarity of molecule
-decrease the lipophilicity- molecule less likely to be reabsorbed in kidney tubule or intestine
parent drug converted into a primary metabolite which may in turn act as a substrate for a second biotransformation that will produce a secondary metabolite
What do phase I reactions do?
creates a functional group or modifies an existing one- provides a chemical handle that makes metabolite more prone to undergoing a synthetic reaction
What does phase II reaction do?
coupling of metabolite with an endogenous moiety such as glucuronic acid, glutathione, sulphate etc.
now more polar and increase molecular weight
larger more charged molecules are much less likely to be reabsorbed than small, non polar ones
What does biotransformation do to product compound?
activity reduced compared to parent compound
What enzymes facilitate phase I?
CP450 and short chain dehydrogenases
Does parent drug need to undergo phase I reaction?
no, depends on chemical structure of parent drug
Creation of functional groups?
oxidation reaction- CP450
also reductases and hydrolytic enzymes
modification reactions?
hydrolysis- esterases and amidases
What do chemically functional groups include?
Hydroxyl, amino and thiol
Where do phase I reactions happen?
liver
gut, small intestine, lung and kidney
IN CELL: smooth endoplasmic reticulum
-some in mitochondria
-cytosol
What intermediates are toxic?
intermediates like quinones and quinone analogues
Why are some intermediates toxic?
- Some of the intermediates are highly electrophilic
- Can covalently modify macromolecules (adducts; proteins and DNA)
- Bioactivation
Why would a drug be given in an inactive (or less active) form (pro-drug)?
useful in overcoming absorption and distribution issues
improve safety if active drug would cause problems at site of administration
due to unpleasant organoleptic (effect on senses) properties of the active drug
Give characteristics of CP450?
some have broad substrate specificty (3A4) , others not
many polymorphic variants of some of cytochrome P450s (variation in gene sequence can have a big impact on activity when it comes to drug metabolism)
mono-oxygenases -most common catalysed reaction is the addition of a single atom of oxygen into an organic substrate
Where do phase 2 reactions happen?
within liver, hepatocytes
extrahepatic too
Give characteristics of phase II?
products are larger, more hydrophillic and are therefore more likely to be excreted
are also almost invariably less pharmacologically active
the products tend to be weak acids -at most physiological pH they will be largely ionised and therefore less likely to be reabsorbed
these conjugates more likely to bind to plasma proteins - which reduces the likelihood of their distribution to other tissues
availibility of cofactors that determine capacity of reaction
what happens when overdose of paracetamol?
excess NAPQI accumulates with resulting liver damage
What is N -acetyl cysteine for?
sulphydryl containing drug that breaks down the mucus that causes problem in the gut and resp tract in cystic fibrosis
Why is N-acetyl cysteine an antidote for paracetomol overdose?
replenishes glutathione and enhances activity of glutathione -S-transferase (enzyme that catalyses the conjugation reaction)
What cycloprotein is important for increasing toxicity of paracetomol?
CYP2E1- if induced paracetomol toxicity is more likely
What things might induce CYP2E1?
St John’s wort herbal medicine
