Download Drug Metabolism

NADPH
S
O2
H 2O
SOH
NADPHCyt. P450
reductase
NADP +
P450
Aromatic hydroxylation
OH
Aliphatic hydroxylation
CH2
CH3
CH2
CH2OH
Epoxidation
Dealkylation
HO
CH3O
+
O
O
NCH3
NCH3
HO
HO
Codeine
Morphine
HCHO
CYP1A
• Metabolize polycyclic hydrocarbons
• Are induced by polycyclic hydrocarbons
– Found in cigarette smoke
– Associated with cancer
• CYP1A1
– is inducible
– extrahepatic
• CYP1A2
– is constitutively expressed only in liver
– Is inducible
CYP1A
• Polymorphisms (primarily CYP1A1)
– Expression polymorphism
– Structural gene polymorphism
• In vivo assay (CYP1A2)
– Caffeine metabolism
CYP 2A
• CYP2A6 and CYP2A13
– CYP2A6 is polymorphic
– Responsible for nicotine metabolism
CYP 2B
•CYP2B6
– CYP2B1 and CYP2B2 are major forms
in rats
–was originally thought to be a minor
form in humans
CYP2C
• CYP2C8, CYP2C9, CYP2C18, and CYP2C19
are major forms in humans
• Hormonally regulated in rodents (growth
hormone)
• Metabolize about 30% of commonly used drugs
– Omeprazole
– Diazepam
• In vivo substrates
– S-mephenytoin (CYP2C19)
– Flurbiprofen (CYP2C9)
CYP2D6
• Metabolize many important drugs
– Codeine
– Dextromethorphan
• Polymorphisms
– Mutation in the structural gene
– Related to increased cancer risk (rapid metabolizers)
• In vivo substrate
– Debrisoquine
– Dextromethorphan
CYP2E1
• Is uncoupled
– Produces superoxide and hydrogen peroxide
• Forms reactive intermediates
– Nitrosamine carcinogens
– acetaminophen
CYP2E1
• Is uncoupled
• Forms reactive intermediates
– Associated with acetaminophen toxicity
• Ethanol inducible
• Polymorphisms
– Linked to cancer
– Role in alcohol-related liver dysfunction
• In vivo substrate
– chlorzoxazone
CYP3A4/5
• Major P450 in humans - metabolizes over
50% of commonly used drugs
• Is inducible by numerous drugs
• CYP3A4 not polymorphic – but wide
variation in activity (due to CYP3A5)
• In vivo substrates (hepatic and intestinal)
– Erythromycin
– Alfentanil
Hydrolysis reactions
• Plasma, liver, kidney, and all tissues
• Esterase
– Succinylcholine apnea
• Amidase
• Epoxide hydrolase
– Found in liver and all tissues
– Both microsomal and soluble forms
– Inducible by phenobarbital and 3methylcholanthrene
Hydrolysis reactions
• Esterase (plasma, liver, and kidney)
– Succinylcholine apnea
• Amidase (liver)
• Epoxide hydrolase
– Found in liver and all tissues
– Both microsomal and soluble forms
– Inducible by phenobarbital and 3methylcholanthrene
Hydrolysis reactions
• Esterase (plasma, liver, and kidney)
– Succinylcholine apnea
• Amidase (liver)
• Epoxide hydrolase
– Found in liver and all tissues
– Both microsomal and soluble forms
– Inducible by phenobarbital and 3methylcholanthrene
Conjugations reactions
(phase 2)
•
•
•
•
•
•
Glucuronidation
Sulfate conjugation
Acetylation
Glutathione conjugation
Methylation
Glycine conjugation
Acetylation
CH3
C O
O
N
C
NH2
NH
NH
Acetyl CoA
N
N-acetyl transferase
C
O
NH
Glutathione conjugation
H
H2
C
S
O
H
OH
H
C
H2
C
NH
C
CH2
CH2
CHNH2
COOH
H
N
H2
C COOH
Methylation
• Methytransferases
• Cytoplasm and endoplasmic reticulum
• S-adenosymethionine
Amino acid conjugation
• Usually as glycine conjugates
• Mitochonria and cytoplasm
Total Body Volume
A
absorption
A
elimination
A
Central compartment
absorption
A
elimination
A
A
distribution
A
One Compartment Model
Intravascular Bolus
[drug] in plasma
mg/100 ml
[drug] in plasma
mg/100 ml
30
20
50.0
5.0
10
0
0
2
4
6
8
Time (h.)
10
12
14
0.5
0
4
8
12
Time (h.)
20
[drug] in plasma
mg/100 ml
[drug] in plasma
mg/100 ml
zero order
30
50.0
zero order
5.0
1st order
0.5
0
4
8
12
Time (h.)
10
first order
0
0
2
4
6
8
Time (h.)
10
12
14
One Compartment Model
Extravascular
100
[drug] in plasma
mg/100 ml
[drug] in plasma
mg/100 ml
30
20
10
1
0
10
0
0
10 20 30 40 50
Time (h.)
10
20
30
Time (h.)
40
50
[drug] in plasma
mg/100 ml
Effect of absorption rate constant
ka=1.39
ka=0.693
20
ka=0.277
ka=0.069
10
0
0
10
20
30
Ti me (h.)
40
50
Two Compartment Model
Intravascular Bolus
75
[drug] in plasma
mg/100 ml
[drug] in plasma
mg/100 ml
100
50
1
0
25
0
0
10
4
8 12 16 20 24
Time (h.)
2
4
6
8
Time (h.)
10
12
14
Two Compartment Model
Extravascular
50
40
[drug] in plasma
m g/Liter
[drug] in plasma
mg/100 ml
100
30
20
10
1
0
10
20
30
40
Time (h.)
10
0
0
4
8
12
Time (h.)
16
20
24
Apparent Volume of
Distribution
[drug] in plasma
mg/100 ml
50.0
Co p
5.0
0.5
0
4
8
12
Time (h.)
Continuous IV Infusion
Multiple IV Administration
Multiple Extravascular
Administration
[drug] in plasma
mg/100 ml
50
0.5
0
Co p
5
4
8
Time (h.)
12