NADPH-Cyt. P450 reductase

P450P450

S

SOH

O2 H2O

e

NADPH

NADP+

Aromatic hydroxylation

OH

Aliphatic hydroxylation

CH2 CH3 CH2 CH2OH

Epoxidation

Dealkylation

O

CH3O

NCH3

HO

O

HO

NCH3

HO

+ HCHO

Codeine Morphine

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 3-

methylcholanthrene

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 3-

methylcholanthrene

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 3-

methylcholanthrene

Conjugations reactions(phase 2)

• Glucuronidation

• Sulfate conjugation

• Acetylation

• Glutathione conjugation

• Methylation

• Glycine conjugation

Acetylation

N C

O

NH

NH2

N C

O

NH

NH

C

CH3

O

Acetyl CoA

N-acetyl transferase

Glutathione conjugation

OS

H2C

HC

H2C

NH

C

CH2

CH2

CHNH2

COOH

HN

H2C COOHH

OHH

Methylation• Methytransferases

• Cytoplasm and endoplasmic reticulum

• S-adenosymethionine

Amino acid conjugation• Usually as glycine conjugates

• Mitochonria and cytoplasm

eliminationA Aabsorption

Total Body Volume

A

distribution

Central compartment

A

A

A Aabsorption elimination

One Compartment Model

Intravascular Bolus

0 2 4 6 8 10 12 140

10

20

30

Time (h.)

[dru

g]

in p

lasm

a

g/1

00 m

l

0 4 8 120.5

5.0

50.0

Time (h.)[d

rug]

in

plas

ma

g/

100

ml

0 2 4 6 8 10 12 140

10

20

30

Time (h.)

[dru

g] i

n pl

asm

a

g/10

0 m

l

zero order

first order

0 4 8 120.5

5.0

50.0

Time (h.)

[dru

g] i

n pl

asm

a

g/10

0 m

l

zero order

1st order

One Compartment Model

Extravascular

0 10 20 30 40 500

10

20

30

Time (h.)

[dru

g] i

n pl

asm

a

g/10

0 m

l

0 10 20 30 40 501

10

100

Time (h.)

[dru

g] i

n pl

asm

a

g/10

0 m

l

Effect of absorption rate constant

0 10 20 30 40 500

10

20

ka=1.39

ka=0.693

ka=0.277

ka=0.069

Time (h.)

[dru

g] i

n pl

asm

a

g/1

00 m

l

Two Compartment Model

Intravascular Bolus

0 2 4 6 8 10 12 140

25

50

75

Time (h.)

[dru

g] i

n p

lasm

a g

/100

ml

0 4 8 12 16 20 241

10

100

Time (h.)

[dru

g] i

n p

lasm

a g

/100

ml

Two Compartment Model

Extravascular

0 4 8 12 16 20 240

10

20

30

40

50

Time (h.)

[dru

g] i

n p

lasm

a g

/100

ml

0 10 20 30 401

10

100

Time (h.)

[dru

g] in

pla

sma

g/L

iter

Apparent Volume of Distribution

0 4 8 120.5

5.0

50.0 Cop

Time (h.)

[dru

g] i

n pl

asm

a

g/10

0 m

l

Continuous IV Infusion

Multiple IV Administration

Multiple Extravascular Administration

0 4 8 120.5

5

50 Cop

Time (h.)

[dru

g] i

n p

lasm

a g

/100

ml