Drug Metabolism and Elimination Flashcards
What are the sites of metabolism in the body?
- Gut lumen
- Gut wall
- Plasma
- Lungs
- Kidneys
- Nerves
- Liver
What can the result of metabolism be?
- Pharmacological deactivaation
- Pharmacological activation
- Type of pharmacological response
- No change in pharmacological activity
- Change in drug uptake
- Change in drug distribution
What does phase 1 metabolism usually involve?
- Oxidation, reduction or hydrolysis- “functionalisation”
- Product often more reactive
WHat does phase 2 metabolism involve?
- Synthetic conjugative reactions
- Hydrophilic, inactive compounds generated (usually)
Where does the majority of phase 1 metabolism occur?
The liver
What are 3 types of phase 1 oxidation reactions?
- Mixed-function oxidase system (cytochrome P450)
- Alcohol dehydrogenase
- Xanthine oxidase
What are 3 types of phase 1 reduction reactions?
- Ketone reduction
- Anaerobic cytochrome P450 metabolism
What are 3 types of phase 1 hydrolysis reactions?
- Ester hydrolysis (e.g. cholinesterases)
- Amide hydrolysis
What enzymes are responsible for the majority of phase 1 metabolisms?
CYP450
Where are cytochrome P450s found?
- Liver (mostly)
- Kidney
- Lung
- Intestine
What does Cytochrome P450 require ?
- NAPDH-CYP450 reductase
- Lipid
- Molecular oxygen
- NADPH
Where can drugs be excreted after phase 2 metabolism?
bIle or urine (water-soluble)
What type of reaction turns aspirin to salicylic acid?
Hydrolysis
What happens to salicylic acid?
- 13% excreted in urine
- 4% oxidised (phase1)
- 34% glucuronidation (phase 2), can be excreted in feces
- 49% glycination (phase2)
What kind of drugs are eliminated more readily?
Hydrophilic over lipophilic
What organ is most responsible for the elimination of drugs and its metabolites?
Kidneys
How are drugs transfered from plasma to bile?
- Organic cation transporters (OCTs)
- Organic anion transport (OATs)
- P-glycoproteins (P-GP)
What can hydrolysis of drug conjugate result in?
Reabsorption of the liberated drug via the enterohepatic circulation
What transporters are thought to be responsible for multi-drug resistance (e.g chemotherapy)?
- P-glycoproteins (P-GP)
How can certain antibiotics interfere with certain drugs?
Gut microbiota facilitates the enterohepatic circulation has been destroyed (e.g oral contraceptives)
What drugs will not be filtered by the glomerulus?
- Drugs above 20 kDa in molecular weight
- Bound to plasma albumin
What percentage of drug will diffuse across the renal tubule if it is freely permeable?
99%
What happens to salicylate clearence as urinary pH increases?
Clearence increases (as it is a weak acid)
What does zero order kinetics mean?
Constant rate or a constant proportion of drug removed per unit time
What is 1st order kinetics?
- Drug is being removed at a constant rate or a constant proportion per unit time (meaningful half-life)
- More drug, faster metabolism
What rule does salicylic acid follow in terms of kinetics?
- Non-linear
- High doses saturate
- Follows first order but can follow zero order at high doses
Clearence and Vd
LEARN again
What is the half life equation?
(ln2 x Vd) / (CL)
What is cleared more quickly aspirin or salicyclic acid?
Salicyclic acid (so lower clearence), higher half-life
What is the most important pharmacokinetic parameter to consider?
Clearence
