1
Q
Metabolism
A
The enzyme mediated alteration of a drug’s structure
2
Q
Metabolism is also referred to as…
A
Biotransformation
3
Q
Where is metabolism found?
A
Liver, Intestine, Stomach, Kidney, Intestinal Bacteria
4
Q
The primary site of drug metabolism is…
A
The liver
5
Q
How does the intestine metabolize drugs?
A
The enterocytes that line the gut are our key metabolizers
6
Q
What does the stomach metabolize?
A
Alcohol
7
Q
Why is drug metabolism important?
A
Metabolism protects humans from a number of environmental toxins as well as playing an important role in synthesizing essential endogenous molecules
8
Q
Exogenous
A
Things that are not natural in our body (alcohol, drugs, steak, cigarets, coffee, etc.)
9
Q
Endogenous
A
Things that are natural in our body (vitamin D synthesis, bile acid synthesis, cholesterol metabolism, steroid hormones, bilirubin)
10
Q
What are the consequences of drug metabolism?
A
- ) Increase water solubility of drugs to promote their excretion (lipo -> hydro)
- ) Inactive drugs (active -> inactive)
- ) Increase drug effectiveness (active -> more active)
- ) Activate prodrugs (drugs that are inactive until metabolized)
- ) Increase drug toxicity
11
Q
1st Order Kinetics for Drug Metabolism
A
Drug metabolism is directly proportional to the concentration of free drug
12
Q
What order of kinetics is “a fraction of drug metabolized per unit time”?
A
1st Order
13
Q
What order of kinetics has more drug metabolizing enzyme then drug?
A
1st Order
14
Q
Zero Order Kinetics
A
Drug metabolism is constant over time
15
Q
What order of kinetics is a constant amount of drug metabolized per unit time?
A
Zero Order
16
Q
What is a good example of a zero order kinetic drug?
A
Ethanol
17
Q
What order of kinetics has more drug then drug metabolizing enzyme?
A
Zero Order
18
Q
1st Pass Metabolism
A
PO drugs can undergo significant metabolism prior to entering the systemic circulation
19
Q
First pass metabolism can occur…
A
- ) Hepatocytes in the liver
- ) Intestinal enterocytes
- ) Stomach
- ) Intestinal bacteria
20
Q
What is the result of 1st pass metabolism
A
Decreased amount of parent drug that enters systemic circulation
21
Q
ER stands for…
A
Extraction Ratio
22
Q
High ER Drugs are…
A
Highly metabolized in the liver
23
Q
High ER Drug characteristics:
A
- Low oral bioavailability (1-20%)
- PO doses are usually much higher than IV doses (compensating for high first metabolism)
- Small changes in hepatic enzyme activity produce large changes in bioavailability
- Very susceptible to drug-drug interactions
24
Q
Low ER Drug characteristics:
A
- Have high oral bioavailability (>80%)
- PO doses are usually similar to IV doses
- Small changes in hepatic enzyme activity have little effect on bioavailability
- Not very susceptible to drug-drug interactions
- Take many passes through the liver via the systemic circulation before they are completely metabolized
25
What are the two phases of metabolism called?
Phase I Metabolism, Phase II Metabolism
26
Phase I Metabolism
Converts lipophilic drugs to more polar molecules (unmasks polar groups like OH or NH2)
27
What types of reactions are involved in Phase I Metabolism?
Oxidation, reduction and hydrolysis reactions
28
What mediates phase I metabolism?
Cytochrome P450 enzymes, esterases and dehydrogenases
29
Metabolites from phase one are how active in comparison to the parent drug?
They are either more, less or equally active. It varies greatly.
30
Phase II Metabolism
Increase the polarity of lipophilic drugs by conjugation reactions (addition of large water soluble molecule to drug)
31
What is included in a conjugate?
Glucuronic acid (sugar), sulfate (SO4), acetate or amino acids (glycine)
32
Metabolites from phase II are how active in comparison to the parent drug?
Less active
33
What is the exception of Phase II Metabolism?
Morphine 6-glucuronide - more potent analgesic (pain reliever) than morphine
34
True or False: some drugs directly enter phase II metabolism?
True
35
Where are phase I drug metabolizing enzymes localized?
The smooth endoplasmic reticulum
36
Where are phase II drug metabolizing enzymes localized?
Predominantly in the cytosol with the exception of glucuronidation which is localized to the smooth ER
37
CYPs
Large family of drug metabolizing enzymes
38
In what phase are CYPs predominant?
Phase I Drug Metabolizing
39
The majority of drug metabolism in the body is performed by
Hepatic CYP enzymes
40
CYPs oxidize drugs by...
Inserting one atom of oxygen into the drug molecule producing water as a by product
41
How many faimilies of CYPs are there?
12 families, 3 accounting for the majority of drug metabolism
42
What is malnutritions effect on CYP activity?
Decreases activity as these enzymes require dietary protein, iron, folic acid and zinc for full activity
43
What does the A in CYP3A4 represent?
The sub-family
44
What does the 3 in CYP3A4 represent?
Family
45
What does the 4 in CYP3A4 represent?
Isozyme
46
What CYP metabolizes the largest fraction of currently marketed drugs?
CYP3A4
47
What are the five phase II drug metabolizing enzymes:
1. ) UDP-glucuronosyltransferases (UGTs)
2. ) Sulfotransferases (SULTs)
3. ) Glutathione S Transferases (GSTs)
4. ) N-acetyltransferases (NATs)
5. ) Thiopurine Methyltransferase (TPMT)
48
UGTs are localized...
In the smooth endoplasmic reticulum
49
What phase are UGTs part of?
Phase II
50
What do UGTs catalyze?
The transfer of a glucuronic acid (sugar) to a drug
51
Why are glucuronidated drugs more easily excreted?
They are more polar
52
How many human UGT enzymes are there?
19
53
What is the reaction for UGT?
Drug + UDP-glucuronic acid -> Drug-glucuronide + UDP
54
Where are SULTs localized?
In the cytosol
55
What phase are SULTs?
Phase II Drug Metabolizing enzymes
56
What do SULTs catalyze?
The transfer of a sulphate group to a hydroxyl group of drugs
57
Why are sulphated drugs more easily excreted?
They are more polar
58
How many human SULT enzymes are there?
11
59
What is the drug reaction for SULT?
Drug + sulphate -> drug-sulfate
60
Where are GSTs localized?
Cytosol or Microsomal
61
What phase are GSTs?
Phase II Drug Metabolizing enzymes
62
What do GSTs catalyze?
The transfer of a glutathione molecule to a drug
63
What is Glutathione (GSH)
Intracellular anti-oxidant
64
How do GSTs render the metabolite less toxic?
They transfer glutathione onto a reactive/toxic drug
65
How many human GSTs are there?
20
66
GST Reaction
Reactive Drug + GSH -> Drug-GSH
67
Where are NATs localized?
Cytosol
68
What phase are NATs?
Phase II
69
What do NATs catalyze?
The transfer of an acetyl group from acetyl CoA to a drug
70
Why do NATs have a variability in drug response?
They are subject to genetic polymorphisms
71
How many human NATs are there?
2: NAT 1 and NAT 2
72
NAT Reaction
Drug + Acetyl-CoA -> Acetylated Drug + CoA
73
Where are TPMT localized?
Cytosol
74
What phase are TPMT?
Phase II
75
What do TPMTs catalyze?
The transfer of a methyl group from S-adenosylmethionine to a drug
76
Why do TPMTs sometimes become unsafe?
They are subject to genetic polymorphisms. This has a dramatic effect on safety
77
TPMT Reaction
Drug + S-adenosylmethionine -> Drug-CH3 + Methionine
78
What are the four factors that affect drug metabolism?
1. ) Age
2. ) Drug interactions (enzyme inducers and enzyme inhibitors)
3. ) Disease state
4. ) Genetic polymorphisms
79
What is the activity of CYP in an infant?
Almost no activity, not until 1 year after birth
80
By what age do infants have the same drug metabolizing enzymes as adults?
Age 2
81
Enzyme Induction
A process where a cell synthesizes an enzyme in response to a drug or other chemical
82
What is the consequence of CYP induction?
Increased drug metabolism
83
What are the consequences of increased drug metabolism?
1. ) Decreased plasma drug concentration
2. ) Decreased drug activity (if metabolite is inactive)
3. ) Increased drug activity (if metabolite is active)
84
What is the consequence of CYP inhibition?
Decreased drug metabolism
85
Decreased drug metabolism results in...
1. ) Higher plasma drug concentration
2. ) Increased therapeutic effect of drugs
3. ) Increased drug toxicity
86
What are 4 diseases that decrease CYP activity?
1. ) Liver disease
2. ) Kidney Disease
3. ) Inflammatory diseases
4. ) Infection
87
What are genetic polymorphisms also known as?
Single Nucleotide Polymorphisms (SNPs)
88
What is a SNP?
A change of a single nucleotide in our DNA
89
What do SNPs affect?
Proteins
90
Phase I SNPs
CYP2C9, CYP2D6
91
CYP2C9
Metabolizes the anticoagulant drug warfarin
92
Results of a polymorphism of CYP2C9
An enzyme with decreased activity, patients require a lower dose of warfarin
93
What happens to a patient with CYP2C9 who is not administered a lowered dosage of warfarin?
Extensive bleeding
94
CYP2D6
Metabolizes codeine to morphine. Morphine is a more potent analgesic than codeine
95
What are the 4 distinct phenotypes that genetic polymorphisms causes in CYP2D6?
- Ultra-rapid metabolizer (UM)
- Extensive Metabolizer (EM)
- Intermediate Metabolizer (IM)
- Poor Metabolizer (PM)
96
What affect do extensive metabolizers have on enzymatic activity?
No effect. Enzymatic activity is normal.
97
Intermediate metabolizers have _____ metabolic activity?
Reduced
98
Poor metabolizers have _____ metabolic activity
No
99
Ultra-rapid metabolizers have _____________ CYP2D6 activity
Significantly increased
100
Phase II SNPs
UGT1A1, NAT2
101
What kind of compound is Glucuronidate?
An anti-cancer compound
102
What affect do polymorphisms in UGT1A1 have on activity?
Decreased activity
103
What risks are increased for patients with a UGT1A1 polymorphism?
Diarrhea and dose limiting bond marrow suppression (potentially fatal)
104
NAT2
Acetylates the drug isoniazid (for tuberculosis), caffeine and various cancer causing chemicals
105
How many different SNPs are in the NAT2 gene?
23
106
How are patients classified as either rapid or slow acetylators?
Based on their genotype
107
What type of acetylator is more susceptible to isoniazid toxicity?
Slow acetylators
108
What type of acetylator is at higher risk for developing cancer?
Slow acetylators
Pharm 2060
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