89 Drug metabolism and elimination Flashcards
Name the different sites of drug metabolism?
- Gut lumen
- Gut wall
- Plasma
- Lungs
- Kidneys
- Nerves
- Liver
Result of metabolism?
- Pharmacological deactivation
- Pharmacological activation
- Type of pharmacological response
- No change in pharmacological activity
- Change in drug uptake
- Change in drug distribution
Where does drug metabolism mainly occur in?
Mainly occurs in liver in 2 phases
What are the two phases of drug metabolism in the liver?
- Phase I metabolism
• Generally oxidation, reduction or hydrolysis
– Introduce/reveal a reactive chemical group
– “Functionalisation”
• Products often more reactive - Phase II metabolism
• Synthetic, conjugative reactions
• Hydrophilic, inactive compounds generated (usually)
Phase I predominately prepares drugs for Phase II metabolism
– Phase II true ‘detoxification’ pathway
What functional groups does Phase I metabolism introduce or unmask?
–OH, -NH2, -SH, -COOH
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 conjugation
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
What are possible sources of excretion?
- Breath
- Urine
- Saliva
- Perspiration
- Feces
- Milk
- Bile
- Hair
The kidneys are the most important organs involved in the elimination of drugs and their metabolites
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)
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, whilst polar 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
• More ionised drug
• Less able to be
reabsorbed
• Eliminated in urine
Zero order kinetics
• Few drugs • Rate of metabolism is constant • Does not vary with amount of drug present • Enzyme saturation – Alcohol dehydrogenase
First order kinetics
- Most drugs
- A constant fraction metabolised/unit time
- Increases proportionately to drug
- More drug, faster metabolism
Kinetics of salicylic acid metabolism?
- Non-linear kinetics
* High doses saturate
Vd (apparent volume of distribution) of a drug =
Total amount of drug in the body/ Blood plasma concentration of drug
Units = L or L/kg
CL (clearance) of a drug =
Sum of all routes of elimination (e.g. metabolism + excretion)
Units = L/h
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.)
Factos that affect metabolism
- Age
- Disease
- Genetic variation
- Other medications
Effect of age on drug metabolism?
- Fetus - maternal protection
- Children - low level of activity
- Elderly - starts to decline
Effect of disease on drug metabolism?
- Dependent on proper liver function - cirrhosis, hepatitis, cancer
- Adequate essential amino acid supply - starvation, cancer
- Other disease conditions - kidney disease, severe burns
Effect of genetic variation on drug metabolism?
- Wide range of CYP phenotypes - rapid, slow, unusual metabolisers
- Race - inherent generalisable variability
Effect of other medications of drug metabolism?
- Induction of metabolic enzymes - reduced effectiveness of drugs
- Inhibition of metabolic enzymes - dietary constituents or drugs
