Metabolism Flashcards
1
Q
A drug that has high Cl is eliminated ____
A
faster
2
Q
Metabolism is considered what types of pathways?
A
elimination
deactivation
detoxification
3
Q
Drug metabolism can result in…
A
- form metabolite more hydrophilic
- deactivate active into inactive
- detoxify toxic xenobiotics
- activate inactive to active
- activate inert into more reactive and toxic
4
Q
Phase I metabolism includes what types of reactions?
A
oxidation
reduction
hydrolysis
5
Q
Oxidation enzymes
A
CYPS, P450s, MAO, ADH, ALDH
6
Q
Reduction enzymes
A
CYPs
7
Q
CYP450s are responsible for metabolism of ___% of drugs
A
75%
8
Q
Where are CYPs?
A
mostly microsomal in ER
9
Q
How do CYPs work?
A
transfer O atom by aid of NADPH CYP450 reductase (POR)
transfers 2 electrons from NADPH
10
Q
Which CYP is involved in metabolism of 50% of all drugs?
A
CYP3A4/5
11
Q
Which CYP metabolism 90% of CYP substrates?
A
1A2 2D6 2C9 2C19 2B6 3A4/5
12
Q
Which CYP metabolism of 70% of all drugs?
A
1A2 2D6 2C9 2C19 2B6 3A4/5
13
Q
Induction and inhibition of CYPs is a major source of what?
A
DDI and drug food interactions
14
Q
CYP2D6, 2B6, 2C9 and 2c19 expression is significantly influenced by what?
A
polymorphisms to give rise to poor and extensive metabolizers
15
Q
CYP2D6 polymorphisms
A
need to screen before you take the drug
- need to know how you metabolize for dose
16
Q
Metabolizing enzymes are located where?
A
- membrane
- microsomal via ER
- mitochondria
- nuclear
- cytosolic
17
Q
What are the 4 outcomes from metabolism of a drug?
A
- active –> inactive
- non-toxic –> toxic
- inactive prodrug –> active drug
- active –> active metabolite
18
Q
What are the enzymatic processes of drug metabolism?
A
Phase I: structural modification
Phase II: conjugation
19
Q
What enzymes are involved with hydrolysis?
A
esterases
amidases
epoxide hydrolases
20
Q
CYPs must contain
A
heme containing proteins
P450 reductases
NADPH
21
Q
What factors influence variability between CYP isoforms?
A
- polymorphisms
- gender
- age
- DDI
- pathological conditions (liver disease)
22
Q
Drugs primarily eliminated intact in urine are ____ suspected to inter and intra individual variation or DDI
A
less
23
Q
Conjugation with polar moieties create what?
A
glucuroinic acid or sulfate groups
24
Q
Conjugation with what decreases polarity?
A
alkyl or acetyl groups
25
Conjugation and kinetics
some have limited capacity (Vmax), cause non linear kinetics
| - saturation
26
UGTs
transfer of glucuronic acid from UDPGA
27
UGT characteristics
- low affinity
- high capacity enzymes
- polar and ionizable metabolites (increase MW)
- facilitates renal and biliary excretion
28
SULTs
transfer of sulfate group from PAPs
29
SULTs characteristics
- high affinity
- low capacity enzymes
- inactivation of steroids and bile acids
30
NATs
transfer of acetyl group from acetyl CoA
31
NATs characteristics
- metabolite less polar than parent
| - polymorphism
32
GSTs
- transfer GSH to reactive electrophilic species (ROS)
| - eventually transformed into mercapturic acid derivatives
33
What is the major source of bacterial metabolism?
gut microflora
34
What are examples of spontaneous biotransformation?
hydrolysis of labile bonds
35
What reactions are catalyzed by gastric acid?
hydrolysis of esters
36
Significance of intestinal metabolism
- orally administered drugs have higher concentrations in enterocytes
- long resident times
- in liver, there are alternative pathways if CYP3A4 is inhibited; in intestine no alternatives!
37
T/F Liver metabolism is more extensive than intestinal metabolism of drugs
False; as extensive
38
Vmax
- max reaction speed at which all enzyme molecules are being used to catalyze the reaction
- defines capacity of the reaction, related to enzyme expression levels (E) and its kcat
39
Kcat
catalytic constant = turnover number
| number of substrate molecules that one molecule of enzyme can convert to product per time
40
Km
- substrate concentration at which reaction rate (v) is half that of Vmax
- defines affinity between substrate and enzyme
41
Decreasing Km = _____ affinity
more
42
Higher Vmax = _____ capacity
higher
43
When [S} << Km...
Cl is concentration independent
1st order
linear
44
At higher [S]...
Cl is concentration dependent
0 order
nonlinear
PK approaches saturation
45
Homotropic cooperativity
- biphasic kinetics
- sigmoidal
- substrate inhibition
46
Heterotrophic acitvation/cooperativity
effector, a different chemical entity than substrate, increase reaction velocity of substrate without affecting enzyme expression
47
Effector molecules
same or different chemical entity bind simultanesouly with substrate molecule to enzyme at distinct sites and affect rate of substrate binding
48
IC50
concentration of inhibitor to reduce enzyme activity toward substrate by 50%
49
What does IC50 depend on?
substrate concentration
50
What is Ki independent of?
substrate concentration
51
Ki or IC50: which can you compare inhibitors regardless incubation conditions?
Ki
52
Competitive inhibition
```
Vmax = no change
Km = increased
Vmax/km = decreased
```
**extent of inhibition decreased or completely reversed by increasing substrate concentration
53
Noncompetitive inhibition
```
Km = no change
Vmax = decreased
Vmax/km = decreased
```
** cannot be reversed by increasing substrate concentration
54
Uncompetitive inhibition
```
Km = decreased
Vmax = decreased
Vmax/km = no change
```
55
Mixed inhibition
```
Km = increase or decrease
Vmax = decreases
```
ratio of the 2 increases or decreases
56
Mechanism based inhibition
- AKA suicide inhibition
- not instantaneous; time dependent
- quasi irreversible non covalent coordination with heme group
- catalytically formed reactive intermediates cause permanent/irreversible inactivation of enzyme
57
Mechanism based inhibition effects
- reaches max effect slowly
| - lasts for a long period of time until a new functional enzyme synthesized
58
Structural alerts may be considered as red flags for what type of inhibition?
mechanism based
59
What does enzyme induction typically affect?
enzyme concentration rather than Kcat (activation/cooperativity)
60
What are some examples of enzyme inducers?
barbiturates, carbamazepine, phenytoin
rifampicin
St John's wort
phenobarbial
61
Autoinduction
carbamazepine induces its own metabolism with time and/or higher doses
62
Enzyme induction effects
slower onset and longer effect
63
How does enzyme induction work?
- activates nuclear receptor
- translocates to nucleus
- binds to response element in promotor region of target gene
- induces its expression
64
T/F only the protein-unbound fraction can be extracted by heptaocytes
True
65
Intrinsic hepatic clearance
- measure pure metabolic capability inherent to hepatic enzymes activity independent of other extra hepatic factors
- sum of all enzymes involved
66
Well stirred model
assumes liver is a single homogenous compartment
| - concentration of unbound drug in effluent is in equilibrium with unbound drug in liver fluid
67
What are the factors that affect hepatic clearance?
- hepatic blood flow (Q)
- protein binding (fu)
- intrinsic clearance (Clint)
68
High E
>0.7
- sensitive to changes in Q
- flow or perfusion limited drugs
- insensitive to changes in fu or Clint
69
Low E
<0.3
- sensitive to changes in fu and Clint
- capacity limited drugs
- insensitive to Q
70
Within low E drugs, are highly protein bound drugs or low protein bound drugs more affected by changes in fu?
highly protein bound drugs (>90%)
71
Well stirred model and AUC
- Not affected by Q in low or high ER drugs in oral drugs!
72
High E and AUC IV
- AUC increase with decreasing Q
| - no change in Clint
73
Low E and AUC IV
- AUC not affected
| - AUC decrease with increasing Clint
74
Which type of drugs are most vulnerable to metabolism based DDI?
highly permeable compounds (perfusion limited)
75
Which type of drugs are most vulnerable to transporter based DDI?
Poorly permeable compounds but good substrates for uptake transporters
76
Which type of drugs are not vulnerable to DDI?
poorly permeable compounds and are not substrates for uptake transporters (diffusion limited)
77
In poorly permeable compounds but good substrates for uptake transporters, hepatic clearance is primarily determined by what?
rate of uptake rather than metabolism
