Transcript Chapter 13. Drug Metabolism Introduction

Chapter 13. Drug Metabolism
Introduction: the process of drugs in the
body includes absorption, distribution,
metabolism and elimination. Drug
metabolism is also named “drug
biotransformation”
Drug
Effects
Absortion
or
Injection
Tissues
Metabolism
Blood
Kidney
Elimination
Important Terms
• Biotransformation: Processes of drugs or
toxins in the body, which may change the
physical, chemical or biological properties
of the drugs or toxins.
• Bioavailability: F, the fraction of the dose
that reaches the systemic circulation. F=1
for IV administration.
• Distribution: Movement of drug from the
central compartment (tissues) to peripheral
compartments (tissues) where the drug is
present.
• Elimination: The processes that
encompass the effective "removal" of
drug from "the body" through excretion
or metabolism.
• Half-Life: the length of time necessary
to eliminate 50% of the remaining
amount of drug present in the body.
Routes of Administration
• Oral
• Injection: Intravenous, Subcutaneous,
Intramuscular, Intraperitoneal
• Transdermal (patch)
• Mucous membranes of mouth or nose
(includes
nasal sprays)
• Inhalation
• Rectal or vaginal
1. Biotransformation and the
enzymes
 The major site for drug biotransformation is
the liver. The extrahepatic sites include: the
lung, kidney, intestine, brain, skin, etc.
 The major organelles for drug
biotransformation is microsome, and others
include cytosol and mitochondria.
 The major enzymes for drug
biotransformation are microsomal enzymes.
Drug Metabolism
Extrahepatic microsomal enzymes
(oxidation, conjugation)
Hepatic microsomal enzymes
(oxidation, conjugation)
Hepatic non-microsomal enzymes
(acetylation, sulfation,GSH,
alcohol/aldehyde dehydrogenase,
hydrolysis, ox/red)
Reactions in biotransformation
Include Phase 1 & Phase 2 Reactions.
Phase 1: involves metabolic oxygenation,
reduction, or hydrolysis; result in changes in
biological activity (increased or decreased)
Phase 2: conjugation—bound by polar
molecules or modified by functional groups,
in almost all cases results in detoxication.
1) The first phase reactions
A. Metabolic oxygenation
Microsomal enzymes catalyze
hydroxylation, dealkylation,
deamination, S-oxidation, Noxidation and hydroxylation,
dehalogenation, etc.
a) Hydroxylation
Hydroxylations include aliphatic and
aromatic hydroxylation
Aliphatic hydroxylation
R CH 2CH 3
OH
R CHCH 3
Examples: ibuprofen, pentobarbital
CO 2H
CO 2H
HO
ibuprofen
O
O
HN
HN
O
N
O
O
N
H
H
pentobarbital
O
OH
Aromatic Hydroxylation
R
nonenzymatic
R
or
OH
OH
R
O
R
O DNA, Pr otein
toxic
reactions
OH
R
unstable
arene epoxide
intermediate
OH
HYL1
epoxide
hydrolase
R
OH
Examples: acetanilide, phenytoin, propranolol
Endogenous substrates: steroid hormones (not aromatic amino acids)
phenytoin
N
N
N
N
HYL1
N
CYP2C8,9
N
O
O
HO
OH
3,4-dihydrodihydroxyphentoin
H
O
O
H
phenytoin
N
N
N
N
O
HO
para-hydroxyphenytoin
O
OH
meta-hydroxyphenytoin
Arene epoxide intermediate produces multiple products
propranolol
H
H
N
O
N
O
OH
OH
OH
H
N
O
OH
OH
b) Dealkylation
Dealkylations include N-, O- and S-dealkylation.
R-X-CH2-R’
[O]
[R-X-CH(OH)-R’]
R-XH + O=CH-R’
X = O, N, S
N-dealkylation
Dealkylation of secondary or tertiary amines
will produce primary amines and aldehydes.
R N
R N
CH2
CH2
CH2
R
CH3
+
-1e -
R N
CH3
CH2
CH2
CH2
CH2
R
R
O2
R N
OH
CH2
-H+
R N
H
CH2
CH2
CH2
CH2
R
R
+ HCHO
O-dealkylation
Dealkylation of ethers or esters will produce
phenols and aldehydes.
Codeine
Morphine
S-dealkylation
S-dealkylation usually produces sulfhydryl group and
aldehyde.
R-S-CH3
S
[O]
[R-S-CH2OH]
CH3
N
N
N
N
6-methylthiopurine
R-SH + HCHO
SH
N
N
N
N
6-thiopurine
+
HCHO
c) Deamination
Deamination may produce ketone and
ammonia.
OH
R C CH 3
NH 2
R CHCH 3
NH 2
O
R C CH 3
+
NH 3
For example, deamination of amphetamine:
NH2
O
+
NH3
d) S-oxidation
S-Oxidation
R
R
S
R2
S O
R2
For example, S-oxidation of chlorpromazine:
O
S
S
N
Cl
N
N
Cl
N
e) N-oxidation
N-Ox ida tion
R
R
NH2
R N
R
NHO H
R N+ R
_
R
O
R
For example, N-oxidation of chlorpheniramine
Cl
Cl
N
N
O
N
N
B. Microsomal oxidases and their action
mechanisms
The enzymes that catalyze the above
oxygenation of drugs are called “mixedfunction oxidase” or “monooxygenase”.
In the reactions, one oxygen is reduced
into water and the other is integrated into
the substrate molecule.
RH + O2 + NADPH + H+
ROH + NADP+ + H2O
Mixed-function oxidase contains
cytochrome P450 (CYP) and NADPH
as electron carrier and hydrogen
provider.
The CYP family: Human CYPs – have
several types and subtypes, named
CYP1, 2, 3…; CYP1a, 1b, and so on.
They are important in drug metabolism.
Human Liver CYPs
CYP
enzyme
1A2
1B1
2A6
2B6
2C
2D6
2E1
2F1
2J2
3A4
4A, 4B
Level
(%total)
~ 13
<1
~4
<1
~18
Up to 2.5
Up to 7
Extent of
variability
~40-fold
Up to 28
~20-fold
~30 - 100-fold
~50-fold
25-100-fold
>1000-fold
~20-fold
2E
S. Rendic & F.J. DiCarlo, Drug Metab Rev 29:413-80, 1997
Drug
NADP+
CYP
R-Ase
ePC
CYP Fe+3
Drug
Drug OH
NADPH
CO
CYP-Fe+2
Drug
CO
h
CYP Fe+3
Drug OH
CYP Fe+2
Drug
eO2
O2
CYP Fe+2
Drug
H2O
2H+
Electron flow in microsomal drug oxidizing system
C. Other oxidases
a) Monoamine oxidase
These enzymes exist in mitochondria.
They catalyze oxidation of amines into
aldehyde and ammonia. For example,
degradation of 5-hydroxytryptamine.
[O]
RCH2-NH2
RCH=NH
H2O
RCHO + NH3
b) Alcohol and aldehyde oxidases
Alcohol
dehydrogenase
R-CHOH
Aldehyde
dehydrogenase
R-CHO
R-COOH
D. Reductions
a) Aldehyde and ketone reductases: these
enzymes catalyze reduction of ketones or
aldehydes to alcohols.
For example:
CCl3CHO
Trichloroacetaldehyde
2H
CCl3CH2OH
Trichloroethanol
The coenzyme may be NADH or NADPH.
b) Reductases for Azo or nitro compounds
 These reductases mainly exist in hepatic
mitochondria with NADH or NADPH as
coenzyme.
H H
2H
N N
N N
2H
Azo
2
NH2
Aniline
NO2
2H
Nitrobenzene
NO
2H
NHOH
2H
NH2
E. Hydrolysis
Esters and amides may be hydrolyzed to
produce acids and alcohol or amine.
O
H2N
C
H2O
H2N
COOH
OCH2CH2N(C2H5)2
H2N
C
NHCH2CH2N(C2H5)2
Amide(Procainamide)
HOCH2CH2N(C2H5)2
Para-aminobenzoic acid
Ester(Procain)
O
+
H2O
H2N
COOH
+
H2NCH2CH2N(C2H5)2
2) The second phase reactions
The second phase reactions of drugs
are also named “Conjugation
Reactions” . These reactions include
glucuronidation, sulfation, acetylation,
methylation and amino acid binding.
Glucuronidation
CO2H
O
OH
HO O
OH
O P O P O CH2
OH O OH
ON
O
NH
O
UDP- -D-glucuronic acid
+
ROH
or
R 3N
UGT
CO2H
OO R
OH
OH
OH
O-glucuronide
CO2H R
+R
ONR
OH
OH
OH
N+-glucuronide
Sulfation
PAPS is the phosphate donor.
O
R O S OH
O
R OH
NH2
N
N
N
N
H
H
HO
O H
H
OH
OH O
OH
O P O S
O
O
(PAPS, 3’-phosphoadenosine5’-phosphosulfate)
Acetylation
Acetylation may reduce the water solubility
of the compounds.
O
Ar NH 2
O
CoA S
R NH 2
R OH
R
SH
Ar N
H
+
Acetyl transferase
O
R O
CH3
CH3
O
O
R N
H
CH3
R
S
CH3
Procainamide
O
H2 N
Unchanged
in Urine, 59%
24% Fast
17% Slow
H
N
Unchanged
in Urine, 85%
N
N
H
3%
O
N
H
O
N
1%
NAPA
0.3%
H
N
O
O
N
H
H
N
O
H2 N
N
H
H
N
Methylation
Methylation of phenols, amines and
biologically active molecules may change
their activity or toxicity. Generally,
methylation reduces the hydrophilicity of
the compound.
S-adenosylmethionine (SAM) is the donor
of methyl group.
Methylation includes N- or O-methylation.
Methylation
SAM
RH
CHOHCH2NH2
-CH3
HO
OH
Norepinephrine
R-CH3
CHOHCH2NH CH3
CHOHCH2NH CH3
-CH3
HO
HO
OH
Epinephrine
O CH3
O-methylepinephrine
(no activity)
2. Factors that affect drug
metabolism
A. Inducers
 Inducers are those that promote drug
metabolism in the body. Most inducers are
lipophilic compounds and have no
specificity in actions.
Examples: barbital, ether, amidopyrine,
miltown (meprobamate), glucocorticoids,
vit. C, etc. Repeated administration of
these drugs may result in drug-resistance.
The mechanism by which inducers enhance
drug metabolism in the body is believed to
be the induction of the enzymes involved in
the drug metabolism.
For example, phenobarbital stimulates
proliferation of SER and increases
production of some enzymes in the
metabolisn of drugs, such as liver CYPs and
UDP-glucuronate transferase, both of which
enhance metabolism of many drugs in the
liver (oxygenation and conjugation).
B. Inhibitors
 Inhibitors are those that inhibit drug
metabolism in the body. Include
competitive and non-competitive inhibitors.
a) A drug inhibits the metabolism of other drugs:
such as chloramphenicol and isoniazid.
They inhibit hepatic microsomal enzymes.
Combined administration of these drugs
and others such as barbitals may increase
the toxicity of the latter.
b) Non-drug compounds inhibit the
metabolism of drugs: such as
pyrogallol (没食子酚). This compound
inhibits o-methylation of epinephrine
and thus enhances the activity of the
hormone in body (it competes with
epinephrine for methyltransferase).
C. Other factors
a) Species difference.
b) Sex, age, nutrition conditions have
effects on drug metabolism.
c) Hepatic functions.
3. Significance of drug
biotransformation
A. Effective removal of drug from the body
through excretion or metabolism. For
example, sulfation and glucuronidation
increase secretion of the drug in urine.
B. Change of the biological activity or
toxicity of drugs in the body. For example,
trichloroacetaldehyde is first reduced into
trichloroethanol and then conjugated by
glucuronate to become a non-toxic
compound.
C. Inactivation of bioactive molecules in the
body. For example, some hormones are
inactivated through biotransformation in
the liver (epinephrine, steroid hormones).
D. Exploration of new drugs. Based on the
mechanisms of biotransformation, it is
possible to design new drugs with longer
half-lives and fewer side-effects.
E. Explanation for the carcinogenic property
of some drugs. For example, after
biotransformation some “non-toxic” drugs
may become toxic or carcinogenic.
N-acetylation may form nitrenium ion
which is a potent carcinogenic agent
CH3
CYP1A2
OH
NH
NH 2
N+
Reactive
Nitrenium ion
NAT2
Carcinogenic DNA Adduct
C O
O
NH
F. The mechanisms of biotransformation
may be used to improve the efficacy of
drugs. For example, those that are mainly
metabolized in the liver may have less
efficacy through oral administration than
IV route.