1. Drug metabolism and elimination Flashcards
Name the different sites of drug metabolism?
– Gut lumen – Gut wall – Plasma – Lungs – Kidneys – Nerves – Liver
What are the two phases of drug metabolism in the liver?
Phase 1 metabolism:
- Generally OXIDATION, reduction or hydrolysis. Introduce/reveal a reactive chemical group
- Products often more reactive
- “functionalisation”
Phase 2 metabolism:
- Synthetic, conjugative reactions
- Hydrophilic, inactive compounds generated
- True “detoxification” pathway
- Leads to product that favours excretion
What are the different oxidations that occur during phase 1 drug metabolism in the liver?
Mixed-function oxidase system (cytochrome P450)
Alcohol dehydrogenase
Xanthine oxidase
What are the different reduction reactions that occur in phase 1 drug metabolism in the liver?
Ketone reduction
Anaerobic cytochrome p450 metabolism
What are the different hydrolysis reactions that occur in phase 1 drug metabolism in the liver?
Ester hydrolysis (e.g. cholinesterases) Amide hydrolysis
Mixed-function oxidase system (CYP450s):
Microsomal (ER) enzymes in…
Consists of?
Requires?
Microsomal (ER) enzymes in the liver, kidney, lung, intestine etc Consists of: -Cytochrome P450 -NAPDH-CYP450 reductase -Lipid (held together in lipid plane)
Requires:
- Molecular oxygen (to allow aerobic reaction)
- NADPH
Characteristics of the products of phase 2 metabolism in the liver?
Detoxified, water-soluble, easily secreted.
Hence suitable for excretion in bile or urine
(Done by various methods of conjugative reactions that overlap in the groups they conjugative)
Name the 6 conjugative reactions that occur in phase 2 drug metabolism?
Glucuronidation Sulfation Glycosidation Methylation Acetylation Glutathione conjugation
Conjugates groups via transferases to make them non-toxic, hydrophilic and easily excreted
What is the process of aspirin metabolism?
Drug –> Derivative –> Conjugate.
In aspirin (drug) –> Salicylic acid (derivative)
–> Glucuronide (Conjugate)
Phase 1= Drug–> Derivative
Via oxidation, hydroxylation, dealkylation, deamination, hydrolysis. Reaction due to environment not enzyme.
Phase 2= Derivative –> Conjugate
Via cojugation
Drugs are eliminated either unchanged or as _______.
In general, hydrophilic drugs eliminated more readily than _____ drugs
Drugs are eliminated either unchanged or as metabolites
In general, hydrophilic drugs eliminated more readily than lipophilic drugs
Name 3 compounds which are involved in the transfer of drugs from plasma to bile?
Organic cation transporters (OCTs)
Organic anion transporters (OATs)
P-glycoproteins (P-GP): Non-specific
Which product of drug metabolism is found concentrated in bile?
Hydrophilic drug conjugates e.g. glucuronides
What is the process of reabsorption of drugs from bile?
Hydrolysis of the conjugate can occur
Reabsorption of the liberated drug by entry to the enterohepatic circulation
Name 2 drugs that enter the enterohepatic circulation?
Oral antibiotics
Oral synthetic oestrogens
What is the process of renal excretion of drugs?
- Glomerular filtration
- Tubular secretion
- Diffusion across renal tubule
- Glomerular filtration
- Filters drugs below 20kDa in molecular weight
- Not filtered if drug is bound to plasma albumin - Tubular secretion
- Via OATs and OCTs
- OATs transport against electrochemical gradient
- Cleared even if bound to plasma albumin - Diffusion across renal tubule
- If tubule freely permeable, 99% of drug reabsorbed.
- (i.e. lipophilic drugs are excreted poorly as they are easily reabsorbed, whilstpolar drugs remain in lumen)
Weak acids more rapidly excreted if urine is _____
Weak acids more rapidly excreted if urine is alkaline
Weak bases more rapidly excreted if urine is _____
Weak bases more rapidly excreted if urine is acidic
What is ion trapping
When a more ionised drug is less able to be reabsorbed so is elimination in urine
Zero order kinetics
Contant amount of drug being removed per unit of time
e.g. Alcohol 1-1.5units/hour
First order kinetics
Constant rate/proportion of drugs removed per unit of time
e.g. most drugs
Difference between zero and first order kinetics?
Zero order: -Few drugs -Rate of metabolism is constant -Does not vary with amount of drug present - Enzyme saturation • Alcohol dehydrogenase
First order:
- Most drugs
- A constant fraction metabolised/unit time
- Increases proportionately to drug
- More drug means faster metabolism
Kinetics of salicylic acid metabolism?
Non-linear kinetics
High doses saturate
Vd (apparent volume of distribution)=
Total amount of drug in the body
/
Blood plasma conc of drug
Units: L or L/Kg
CL (clearance)=
The sum of all routes of elimination (e.g. metabolism + excretion)
Units: L/hr
t1/2=
ln2 x Vd
/
CL
Compare the Vd and CL of aspirin to salicylic acid?
Aspirin:
Volume of distribution (Vd) 10.5 L
Clearance (CL) 39 L/h
Salicylic acid:
Volume of distribution (Vd) 11.9 L
Clearance (CL) 3.6 L/h (dose dep.)
HIGHER HALF L IFE as clearance is lower. So will take longer for inital value to reduce to 1/2
Factos that affect metabolism/
Age
disease
other meds
genetic variation
Effect of age on drug metabolism?
Foetus: Maternal protection
Children: Low level of activity
Elderly: Starts to decline
Effect of genetic variation on drug metabolism?
Wide range of CYP phenotypes: Rapid,s low, unusual metabolisers
Race: Inherent generalisable variability
Effect of disease on drug metabolism?
Dependent on proper liver function: E.g. cirrhosis, hepatitis, cancer
Adequate essential amino acid supply: e.g. starvation, cancer
Other: Kidney disease, burns
Effect of other medications of drug metabolism?
Induction of metabolic enzymes: Reduced effectiveness of drugs
Inhibition of metabolic enzymes: Dietary constituents or durgs
Result of metabolism
Pharmacological deactivation Pharmacological activation Type of pharmacological response No change in pharmacological activity Change in drug uptake Change in drug distribution
Metabolism aim?
Hydrophilic, inactive compounds for excretion in faeces/urine
