Chapter 13. Drug Metabolism Introduction: the process of drugs in the body includes ab sorption, distribution, metab olism and elimination. Drug m etabolism is also named “drug biotransformation” D rug Blood Tissues K idney Effects M etabolism Elim ination A bsortion or Injection
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Chapter 13. Drug Metabolism Introduction: the process of drugs in the body includes absorption, distribution, metabolism and elimination. Drug metabolism.
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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 Blood
Tissues
Kidney
Effects
Metabolism
Elimination
Absortionor
Injection
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, Subcutaneou
s, Intramuscular, Intraperitoneal• Transdermal (patch)• Mucous membranes of mouth or nos
e (includesnasal 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.
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, N-oxidation and hydroxylation, dehalogenation, etc.
a) Hydroxylation Hydroxylations include aliphatic and aro
matic hydroxylation
E x a m p l e s : i b u p r o f e n , p e n t o b a r b i t a l
Aliphatic hydroxylation
R CH 2 CH 3 R CHCH 3
OH
i b u p r o f e n
CO 2 H CO 2 H
HO
p e n to b a r b ita l
HN
N
O
O
H
O
HN
N
O
O
H
O OH
E x a m p le s : a c e ta n ilid e , p h e n y to in , p ro p ra n o lo lE n d o g e n o u s s u b s tra te s : s te ro id h o rm o n e s (n o t a ro m a tic a m in o a c id s )
A ro m a tic H y d ro x y la t io n R
unstable arene epoxideintermediate
non-enzymatic
HYL1epoxide
hydrolase
R OH
OH
R OH
O DNA, Proteintoxic
reactions
O
R
R
OH
R
OH
or
phenyto in
A rene epoxide in term ediate produces m ultip le products
N
N
O
CYP2C8,9 N
N
O
OH
H
HYL1
phenytoin
3,4-dihydro-dihydroxyphentoin
N
N
O
HO
N
N
O
OH
N
N
O
HO OH
para-hydroxyphenytoin meta-hydroxyphenytoin
propranolol O
N
OH
H
ON
OH
H
OH
ON
OH
H
OH
b) Dealkylation
Dealkylations include N-, O- and S-dealkylation.
R-X-CH2-R’
[R-X-CH(OH)-R’]
R-XH + O=CH-R’
[O]
X = O, N, S
N-dealkylationDealkylation of secondary or tertiary amines
will produce primary amines and aldehydes. R N
CH2
CH2
R
CH2
OH
R NCH2
CH2
R
CH2
R NCH2
CH2
R
CH3 R NCH2
CH2
R
CH3+
O 2
-H+-1e-
HCHO+R N
CH2
CH2
R
H
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 [R-S-CH2OH] R-SH + HCHO N
N
N
N
SCH3
N
N
N
N
SH
HCHO+
6-methylthiopurine 6-thiopurine
[O]
c) DeaminationDeamination may produce ketone and ammon
ia. RCHCH3
NH2
RC
NH2
CH3
OH RCCH3
O+ NH3
NH2 ONH3+
For example, deamination of amphetamine:
d) S-oxidation S-Oxidation
SR
R2
SR
R2
O
For example, S-oxidation of chlorpromazine: S
N Cl
N
S
N Cl
N
O
e) N-oxidation N-Oxidation
R NH2 R NHOH
R NR
RR N
+
RR
O_
N
N
Cl
N
N
Cl
O
For example, N-oxidation of chlorpheniramine
B. Microsomal oxidases and their action mechanisms
The enzymes that catalyze the above oxygenation of drugs are called “mixed- function 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
Level (%total)
Extent of variability
1A2 ~ 13 ~40-fold 1B1 <1 2A6 ~4 ~30 - 100-fold 2B6 <1 ~50-fold 2C ~18 25-100-fold 2D6 Up to 2.5 >1000-fold 2E1 Up to 7 ~20-fold 2F1 2J2 3A4 Up to 28 ~20-fold 4A, 4B
2E
S. Rendic & F.J. DiCarlo, Drug Metab Rev 29:413-80, 1997
Electron flow in microsomal drug oxidizing system
CO
h
CO
h
CO
hCYP-Fe+2
Drug
CO
CYP-Fe+2
Drug
CO
O2O2
e-
e-
2H+
H2O
2H+
H2O
DrugDrug
CYPR-Ase
NADPH
NADP+
CYPR-Ase
NADPH
NADP+
OHDrug OHDrug OHDrug
CYP Fe+3CYP Fe+3CYP Fe+3
PCPCDrug
CYP Fe+2
DrugCYP Fe+2
Drug
CYP Fe+2
Drug
O2
CYP Fe+2
Drug
O2
CYP Fe+3
OHDrug
CYP Fe+3
OHDrug OHDrug
C. Other oxidases a) Monoamine oxidaseThese enzymes exist in mitochondria. They catalyze oxidation of amines into al
dehyde and ammonia. For example, degradation of 5-hydroxytryptamine.
RCH2-NH2 RCH=NH RCHO + NH3
[O] H2O
b) Alcohol and aldehyde oxidases
R-CHOH R-CHO R-COOH
Alcohol dehydrogenase
Aldehyde dehydrogenase
D. Reductions
a) Aldehyde and ketone reductases: these enzymes catalyze reduction of ketones or aldehydes to alcohols.
For example:
CCl3CHO CCl3CH2OH
The coenzyme may be NADH or NADPH.
2H
Trichloroacetaldehyde Trichloroethanol
b) Reductases for Azo or nitro compounds These reductases mainly exist in hepatic
mitochondria with NADH or NADPH as coenzyme.
N N N N
H H
NH2
2H 2H2
NO2 NO NHOH NH2
2H 2H2H
Azo
Nitrobenzene
Aniline
E. Hydrolysis
Esters and amides may be hydrolyzed to produce acids and alcohol or amine.
H2N CO
OCH2CH2N(C2H5)2
H2N COOH HOCH2CH2N(C2H5)2+H2O
H2N CO
NHCH2CH2N(C2H5)2
H2O+ H2NCH2CH2N(C2H5)2H2N COOH
Ester(Procain)
Amide(Procainamide)
Para-aminobenzoic acid
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 O
OH
OHOOH
CO2H
P O P O
O
HO
OH
O
CH2
O NNH
O
O
OOH
OHOH
CO2HO R
+ ROH
orR3N
UGT
UDP- -D-glucuronic acidO
OH
OHOH
CO2HN+ R
R
R
O-glucuronide
N+-glucuronide
SulfationPAPS is the phosphate donor.
R OHR O S OH
O
O H H
NH2
N
NN
N
OH
O
H HHO
O P
OH
O
O SOH
O
O
(PAPS, 3’-phosphoadenosine-5’-phosphosulfate)
Acetylation Ar NH2
R SH
R OH
R NH2
+
Ar NCH3
O
H
Acetyl transferase
CoA SO
R NO
CH3H
R OO
CH3
R SO
CH3
Acetylation may reduce the water solubility of the compounds.
P r o c a i n a m i d e
U n c h a n g e di n U r i n e , 5 9 %
3 %2 4 % F a s t1 7 % S l o w
U n c h a n g e di n U r i n e , 8 5 %
N A P A
0 . 3 %
1 %
H 2 N
O
N
H
N N
O
N
H
N
O
H H 2 N
O
N
H
N
H
NO
N
H
N
O
H H
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.
A. Inducers Inducers are those that promote drug meta
bolism 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 metabo
lism 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
NH2 NH
OHNH
O
C OCH3
N+
NAT2CYP1A2
Reactive Nitrenium ion
Carcinogenic DNA Adduct
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.