DRUG METABOLISM
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INDIAN DENTAL ACADEMY Leader in continuing dental education www.indiandentalacademy.com
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Transformation of Xenobiotics by Biological Systems
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IMPLICATIONS FOR DRUG METABOLISM
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IMPLICATIONS FOR DRUG METABOLISM
1.
Termination of drug action
2.
Activation of prodrug
3.
Bioactivation and toxication
4.
Carcinogenesis
5.
Tetratogenesis
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Termination of Drug Action
atropine
propranolol (active)
tropic acid and tropine
→
hydroxypropranolol (active) www.indiandentalacademy.com
Termination of Drug Action
Conversion of drug to active metabolite to active metabolite to inactive metabolite
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Activation of Prodrug
L-dopa
Dopamine
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Inactive Terfenadine is Converted to its Active Metabolite Fexofenadine activation of prodrug
terfenadine
fexofenadine
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Some Xenobiotics Are Metabolized to Carcinogenic Agents carcinogenesis
• 3,4 Benzopyrene • Aflatoxin • N-Acetylaminoflluorene
Metabolites of these agents interact with DNA
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Small Amounts of Acetaminophen is Converted to the Reactive Metabolite N-Acetylbenzoquinoneimine bioactivation
Bioactivation of acetaminophen; under certain conditions, the electrophile Nacetylbenzoquinoneimine reacts with tissue macromolecules, causing liver necrosis. www.indiandentalacademy.com
Thalidomide is a Teratogen teratogensis
– THALIDOMIDE: Fetal malformations in humans, monkeys, and rats occur due to metabolism of the parent compound to a teratogen. This occurs very early in gestation.
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FACTORS AFFECTING DRUG METABOLISM
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Factors Affecting Drug Metabolism • • • • • • • • • •
Age Diet Genetic Variation State of Health Gender Degree of Protein Binding Species Variation Substrate Competition Enzyme Induction Route of Drug Administration
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Factors Affecting Drug Metabolism
• Route of drug administration – Oral versus systemic administration
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Many Drugs Undergo First Pass Metabolism Upon Oral Administration • Oral administration • Drug travels from gut to portal vein to liver • Vigorous metabolism occurs in the liver. Little drug gets to the systemic circulation • The wall of the small intestine also contributes to first pass metabolism
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ORGAN SITES OF DRUG METABOLISM
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Organ Sites of Drug Metabolism
• • • • • • •
Liver Small intestine Kidney Skin Lungs Plasma All organs of the body
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CELLULAR SITES OF DRUG METABOLISM
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Cellular Sites Of Drug Metabolism
• • • •
Cytosol Mitochondria Lysosomes Smooth endoplasmic reticulum (microsomes)
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KINETICS OF DRUG METABOLISM
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80
Velocity Of Metabolism Of A Drug
70
Velocity (ng/g tissue/min)
60 50 40 30 20 10 0 0
10
20
30
40
[Drug] mM
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50
60
70 D:\summer1\Kmx1.pzm
Velocity Of Metabolism Of A Drug 80 70
Velocity (ng/g tissue/min)
60
zero order metabolism
50 40 30 20 10 0 0
first order metabolism 5 10 15 20 25 30 35 40 45 50 55 60
[Drug] mM www.indiandentalacademy.com
Kmx2.pzm
First Order Metabolism A drug may be given in doses that produce blood concentrations less than the Km of the enyzme for the drug.
v = Vmax [C] Km + [C] When then
Km >>> [C], v = Vmax [C] , Km
and
v Îą [C]
Metabolism of the drug is a first order process. A constant fraction of the remaining drug is metabolized per unit time. Most drugs are given at concentrations smaller than the Km of the enzymes of their metabolism. www.indiandentalacademy.com
Velocity Of Metabolism Of A Drug 80 70
Velocity (ng/g tissue/min)
60
zero order metabolism
50 40 30 20 10 0 0
first order metabolism 5 10 15 20 25 30 35 40 45 50 55 60
[Drug] mM www.indiandentalacademy.com
Kmx2.pzm
Zero Order Metabolism A drug may be given in doses that produce blood concentrations greater than the Km of the enyzme for the drug.
v = Vmax [C] K m + [C] When [C] >>> Km, then
v = Vmax [C] , [C]
and
v = Vmax
Metabolism of the drug is a zero order process. A constant amount of the remaining drug is metabolized per unit time. Phenytoin undergoes zero order metabolism at the doses given. www.indiandentalacademy.com
Velocity Of Metabolism Of A Drug 80 70
Velocity (ng/g tissue/min)
60
zero order metabolism
50 40 30 20 10 0 0
first order metabolism 5 10 15 20 25 30 35 40 45 50 55 60
[Drug] mM www.indiandentalacademy.com
Kmx2.pzm
Velocity
(ng/g tissue/min )
Velocity Of Metabolism Of Three Drugs By The Same Enzyme 70
60 50
Drug A Drug B Drug C
40 30 20 10 0 0
10
20
30
40
50
[Drug] mM www.indiandentalacademy.com
60
70
80
90
PHASES OF DRUG METABOLISM
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Phase I Metabolism Polar groups are exposed on or introduced to a molecule
R
ROH
R
RCOOH
R
RSH
R
RNH2
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Phase I Reactions
OXIDATION REDUCTION HYDROLYSIS
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Phase II Metabolism A molecule endogenous to the body donates a portion of itself to the foreign molecule
D+ENDOX
DX+ENDO
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Patterns of Drug Metabolism • Parent molecule → Phase 1 metabolism • Phase 1 metabolite → Phase 2 metabolism • Parent molecule → Phase 2 metabolism • Phase 2 metabolite → Phase 1 metabolism Some drugs are not metabolized, for example, gallamine and decamethonium. Atracurium undergoes spontaneous hydrolysis. www.indiandentalacademy.com
PHASE I METABOLIC PATHWAYS
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Microsomal Oxidation
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Preparation Of Microsomes
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Cytochrome P450
fp = NADPH cytochrome P450 reductase, or NADH cytochrome b5 reductase www.indiandentalacademy.com
Oxidation Of Drugs By Cytochrome P450
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Oxidation Of Drugs By Cytochrome P450
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Aliphatic Oxidation
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Aromatic Hydroxylation (1)
acetanilid
p-hydroxyacetanilid
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Aromatic Hydroxylation (2)
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N-Dealkylation
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O-Dealkylation
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S-Demethylation
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Oxidative Deamination
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S-Oxidation
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N-Oxidation
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N-Hydroxylation
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N-Hydroxylation of AAF
N-Hydroxylation of AAF is the first metabolic step towards the development of a carcinogenic agent www.indiandentalacademy.com
Oxidative Dehalogenation
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Desulfuration
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Desulfuration
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ISOENZMYES OF CYTOCHROME P450 CYP1A1
CYP2D6
CYP1A2
CYP2AE1
CYP2A6
CYP3A4
CYP2B_
CYP3A5
CYP2C9
CYP3A7
CYP2C19
CYP4A_
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Cytochrome P450 3A4 (CYP3A4)
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CYP3A4 • CYP3A4 is responsible for metabolism of 60% of all drugs • It comprises approximately 28% of hepatic cytochrome P450 • Metabolizes terfenadine • Ingestion of grapefruit juice reduces expression of this enzyme • Inhibited by some regularly used drugs
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Some Drugs That Inhibit CYP3A4 • Macrolide antibiotics – Erythromycin – Clarithromycin – Other such agents
• Antifungal agents – Ketoconazole – Itraconazole – Other such agents
• HIV protease inhibitors www.indiandentalacademy.com
CYP3A4
• Ketoconazole and terfenadine can produce a drug interaction with fatal consequences.
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CONVERSION OF TERFENADINE TO FEXOFENADINE
O2, NADPH
CYP3A4
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AN INGREDIENT IN GRAPEFRUIT JUICE INHIBITS CYP3A4
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Grapefruit Juice Increases Felodipine Oral Availability in Humans by Decreasing Intestinal CYP3A Protein Expression
Hours www.indiandentalacademy.com
J.Clin. Invest. 99:10, p.2545-53, 1997
6',7', - Dihydroxybergamottin
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Grapefruit Juice Consumption Blocks Terfenadine Metabolism to Fexofenadine
X
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CYP3A4 And P-Glycoprotein • P-Glycoprotein and CYP3A4 control oral bioavailability of many drugs • P-Glycoprotein and CYP3A4 share many substrates and inhibitors
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CYP2D6 is an Enzyme with Polymorphisms • Approximately 70 nucleotide polymorphisms are known • Four phenotype subpopulations of metabolizers* – Poor metabolizers (PM) – Intermediate metabolizers (IM) – Extensive metabolizers (EM) – Ultrarapid metabolizers (UM) • Variations according to racial background • More than 65 commonly used drugs are substrates • Codeine is a well known substrate www.indiandentalacademy.com * The Pharmacological Basis of Therapeutics
Codeine is a Substrate of CYP2D6
-CH3
(methyl morphine)
Consider the variation in codeine’s metabolism among PM, IM, EM, UM individuals www.indiandentalacademy.com
CYP2C9 • Metabolizes some 16 commonly used drugs • Warfarin and phenytoin are among the substrates • Two allelic variants are known: metabolizes substrates 5% to 12% of the wild type enzyme – Warfarin clearance is greatly reduced in individuals possessing the allelic variants • Dose adjustments are required for drugs in individuals who have the mutant enzymes
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CYP2C19 • S-mephenytoin is a substrate
– (4-hydroxylation at the phenyl ring) • As much as eight allelic variants identified – All are nonfunctional proteins • Poor metabolizers of S-mephenytoin lack 4-hydroxylase activity, but N-demethylation to nirvanol is an alternative but slow metabolic pathway – Dose adjustments must be made for poor metabolizers of S-mephenytoin and for other drugs that are substrates for this enzyme
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CYP1A1 • Polycyclic hydrocarbons are among its substrates • Inducers include – Polycyclic hydrocarbons such as 3,4,-benzopyrene, 3-methylcholanthrene, etc. – Charcoal broiled foods (polycyclic hydrocarbons)
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CIMETIDINE Inhibits CYP450 Metabolism Of Many Drugs
Warfarin
Triazolam
Phenytoin
Chlordiazepoxide
Metoprolol
Carbamazepine
Labetalol
Quinidine
Quinidine
Ethanol
Caffeine
Tricyclic antidepressants
Lidocaine Theophylline
Metronidazole
Alprazolam
Calcium channel blockers
Diazepam
Diazepam
Flurazepam
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Sulfonylureas
NONMICROSOMAL OXIDATIONS ALCOHOL DEHYDROGENATION ALDEHYDE DEHYDROGENATION XANTHINE OXIDATION DIAMINE OXIDATION MONOAMINE OXIDATION
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Nonmicrosomal Oxidations Alcohol dehydrogenation is conducted by the enzyme alcohol dehydrogenase (cytosolic) Aldehyde dehydrogenation is conducted by the enzyme aldehyde dehydrogenase (cytosol and mitochondria) Xanthine oxidation is conducted by the cytosolic enzyme xanthine oxidase. Diamine oxidase (cytosolic) oxidizes histamine and diamines such as cadaverine and putrescine. Monoamine oxidation is conducted by mitochondrial monoamine oxidase (norepinephrine, epinephrine, dopamine and serotonin are endogenous substrates. www.indiandentalacademy.com
Monoamine Oxidase Metabolism of Serotonin
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Some Popular Substrates of Monoamine Oxidase
• • • • •
Serotonin Epinephrine Norepinephrine Dopamine Tyramine (found in certain foods)
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Diamine Oxidase
cadaverine
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Alcohol Dehydrogenase
• A soluble enzyme, found almost exclusively in the parenchymal cells of the liver • Converts ethanol to acetaldehyde • Converts methanol to formaldehyde • Converts ethylene glycol to its respective aldehyde metabolites • Is inhibited by pyrazole
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Alcohol Dehydrogenase
CH3CH2OH + NAD+ → CH3CHO + NADH + H+ ethanol
acetaldehyde
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Aldehyde Dehydrogenase
CH3CHO + NAD+ → CH3COOH + NADH + H+ acetaldehyde
acetate
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XANTHINE OXIDASE
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Xanthine Oxidase
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REDUCTION
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NitroREDUCTION Reduction NITRO
RNO2
RNH2
MICROSOMES AND CYTOSOL Microsomes and cytosol
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Nitro Reduction
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Azo Reduction
AZO REDUCTION RN=NR'
RNH2 + R'NH2
Microsomes and cytosol
MICROSOMES AND CYTOSOL www.indiandentalacademy.com
Azo Reduction
Microsomes and cytosol
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Alcohol Dehydrogenation
Cytosol
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DIHYDROPYRIMIDINE DEHYDROGENASE
5-Fluorouracil
DPYD
5-Fluoro-5,6-dihydrouracil
• DPYD – Inactivates 5-fluorouracil by ring reduction – Inherited deficiency of this enzyme leads to 5-fluorouracil toxicity – Enzyme deficiency can be detected by enzymatic or molecular assays using white blood cells
5-fluorouracil www.indiandentalacademy.com
HYDROLYSIS
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Amide Hydrolysis
AMIDE HYDROLYSIS RCONR'R"
RCOOH+ HNR'R"
Microsomes and cytosol
MICROSOMES AND CYTOSOL
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Ester Hydrolysis ESTER HYDROLYSIS
RCOOR'
RCOOH + R'OH
MICROSOMES AND CYTOSOL
Microsomes and cytosol
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Ester Hydrolysis
Enalaprit
Microsomes and cytosol
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EPOXIDE HYDROLASE
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Epoxide Hydrolase • A microsomal enzyme
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Epoxide Hydrolase
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PHASE II METABOLIC PATHWAYS
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PHASE 2 METABOLISM
A molecule endogenous to the body donates a portion of itself to the foreign molecule
D+ENDOX
DX+ENDO
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PHASE II REACTIONS Glucuronidation Sulfate Conjugation Acetylation Glycine Conjugation Methylation Transulfuration Glutathione Conjugation Mercapturic Acid Synthesis
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GLUCURONIDATION
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Uridine-5’-ι-D-glucuronic Acid
The microsomal enzyme glucuronyl transferase conducts the donation of glucuronic acid from the endogenously synthesized UDPGA to various substrates to form glucuronide conjugates. www.indiandentalacademy.com Examples of such substrates are morphine and acetaminophen.
UDP-α-D-Glucuronsyltransferase • • • • •
Is also called glucuronyl transferase A microsomal enzyme Substrates are called aglycones Conducts phase 2 metabolic reactions Products are called glucuronides
• Glucuronides formed
–
RN-G; RO-G; RCOO-G; RS-G; RC-G
• Bilirubin is an endogenous substrate • Induced by phenobarbital www.indiandentalacademy.com
Glucuronidation of Benzoic Acid
UGT= UDP-Îą-D-Glucuronsyltransferase www.indiandentalacademy.com
Glucuronidation of Aniline
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Glucuronidation of p-Hydroxyacetanilid
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Morphine Metabolism
→ Morphine → Morphine
Morphine -6-glucuronide (active metabolite) Morphine -3-glucuronide (inactive metabolite)
A small amount of morphine undergoes N-demethylation www.indiandentalacademy.com
Morphine Metabolism
Morphine -3-glucuronide is the major metabolite www.indiandentalacademy.com
Induction Of UDP-α-D-Glucuronyl Transferase
• Induced by phenobarbital • Induced by 3-methylcholanthrene
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Glucuronidation in the Cat
• The cat can glucuronidate bilirubin but cannot glucuronidate phenolic compounds such as phenol and napthol
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SULFATE CONJUGATION
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Sulfate Conjugation • Conducted by the soluble enzyme sulfotransferase • Endogenous donor molecule to conjugation is 3’-phosphoadenosine-5’-phosphosulfate (PAPS) • Conjugates are ethereal in character • Noninducible
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3’-Phosphoadenosine-5’-phosphosulfate (PAPS)
The cytosolic enzyme sulfotransferase conducts the donation of sulfate from the endogenously synthesized PAPS to various substrates to form sulfate conjugates. An example of such substrate www.indiandentalacademy.com is acetaminophen.
Sulfate Conjugation of p-Hydroxyacetanilid
PAP: 3’-phosphoadenosine- 5’-phosphate www.indiandentalacademy.com
MINOXIDIL METABOLISM
MINOXIDIL
MINOXIDIL N-O-SULFATE
(inactive)
(active metabolite)
MINOXIDIL N-O-GLUCURONIDE (inactive metabolite) www.indiandentalacademy.com
Species Differences in Sulfate Conjugation • Some species are deficient in the sulfate conjugation pathway – Pig – Opposum
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N-ACETYLATION
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N-Acetyltransferase • A soluble enzyme • Isoniazid is a substrate • Genetic variation occurs
– Some individuals are fast acetylators – Some individuals are slow acetylators • Acetyl coenzyme A is the endogenous donor molecule
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Acetyl CoA
Various acetylases, for examples, choline acetylase and N-acetyl transferase, all soluble enzymes, conduct the transfer of the acetyl group of acetyl CoA to various substrates. For example, N-acetylation of isoniazid. Genetic polyporphism occurs with N-acetyltransferase. www.indiandentalacademy.com
N-Acetyltransferase
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N-Acetyltransferase • The dog cannot acetylate aromatic amino compounds because it lacks the appropriate isoenzyme of NAT
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SUGAR CONJUGATION
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Conversion of 6-Mercaptopurine to a Nucleotide
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METHYLATION
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S-Adenosylmethionine
Cytosolic enzymes such as catechol-O-methyl transferase (COMT) and phenylethanolamine-N-methyl transferase (PNMT) conducts the donation of the methyl group from the endogenously synthesized SAM to various substrates to form methylated conjugates. Norepinephrine is N-methylated by PNMT to form epinephrine. Norepinephrine, www.indiandentalacademy.com epinephrine, dopamine, and L-DOPA are O-methylated by COMT.
Methyltransferases • A family of soluble enzymes that conducts
– – –
N-methylation; N-CH3 O-methylation; O-CH3 S-methylation; S-CH3
• S-adenosylmethionine (SAM)is the endogenous donor molecule. It is demethylated to S-adenosylhomocysteine
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N-Methyltransferases PNMT- Phenylethanolamine-N-methyltransferase Norepinephrine
PNMT SAM
Epinephrine
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O-Methylation Of Catecholamines
COMT- catechol-O-methyltransferase
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O-Methylation of Norepinephrine COMT- catechol-O-methyltransferase
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S-Methylation of 6-Mercaptopurine
TPMT - thiopurinemethyltransferase; some individuals are deficient in this enzyme that is critically important for the metabolism of this agent www.indiandentalacademy.com
METABOLISM OF MERCAPTOPURINE (1) 6-Mercaptopurine
TMPT
6-Methylmercaptopurine
• TMPT -Thiomethylpurinetransferase – Conducts S-methylation of the substrate
– Found in RBC’s – Isoforms exist • active enzyme • inactive enzyme
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AMINO ACID CONJUGATION
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AMINO ACID CONJUGATION
(mitochondria) www.indiandentalacademy.com
Multiple Metabolic Pathways Exist for Aspirin’s Metabolism
Hydolysis of aspirin produces salicyclic acid, as seen in the next slide www.indiandentalacademy.com
Salicyluric Acid is the Glycine Conjugate of Aspirin
Salicyluric acid, the glycine conjugate of salicyclic acid, is the main metabolite of aspirin. Approximately 76% of aspirin is metabolized through amino acid conjugation. www.indiandentalacademy.com
Acetyl Salicylic Acid (Aspirin) Metabolism • Salicylic acid the hydrolytic product of acetyl salicylic acid. Salicylic acid is further metabolized • Salicyl uric acid is the glycine conjugate and the main metabolite of aspirin. About 75% of aspirin is metabolized by this pathway • Other metabolites of aspirin – the acyl glucuronide conjugate of salicylic acid (salicylic acid glucuronide) – the phenol glucuronide conjugate of salicylic acid (salicyl phenol glucuronide) – the ring hydroxylated product of salicylic acid (gentisic acid) – the ring hydroxylated product of the glycine conjugate (gentisuric acid
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TRANSULFURATION
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TRANSULFURATION
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GLUTATHIONE CONJUGATION
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DRUG INTERACTION WITH GLUTATHIONE
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mercapturate metabolite of drug
MERCAPTURIC ACID FORMATION • Conjugation of substrate to glutathione by the enzyme glutathione transferase • Hydrolytic removal of glutamic acid by glutamyl transpeptidase • Hydrolytic removal of glycine by cysteinyl glycinase • Acetylation of the cysteinyl substrate by N-acetyltransferase to form the N-acetylated cysteinyl conjugate of substrate; substrate referred to as a “mercapturate”
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ACETAMINOPHEN METABOLISM
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Bioactivation of Acetaminophen
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ACETAMINOPHEN AND ITS PHASE II METABOLITES
The sulfate and glucuronide conjugates of acetaminophen are the major metabolites. High doses of acetaminophen can exhaust the metabolic pathways that produce these conjugates, allowing more of the parent drug to undergo the phase I metabolic pathway which is involved in bioactivation and toxication. www.indiandentalacademy.com
ACETAMINOPHEN AND ITS PHASE I METABOLITES
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ACETAMINOPHEN AND ITS PHASE I METABOLITES- pt2
The minor metabolite (4% of acetaminophen), N-hydroxyacetaminophen, is always produced by microsomal cytochrome P450. It rearranges to the electrophile N-acetylbenzoquinoneimine, which in turn reacts with the sulfhydryl group of glutathione. Acetaminophen mercapturic acid is the final metabolite. If tissue glutathione stores are depleted as a result of fasting, intake of excessive doses of acetaminophen or through induction of CYP2E1 as a result of chronic intake of ethanol, the quinone interacts with nucleophilic sites of cellular macromolecules, such as proteins. Liver necrosis is the result. Regular intake of acetaminophen during fasting or chronic ethanol intake should be avoided. N-acetylcysteine is the antidote for acetaminophen poisoning. It reacts with the electrophile. A small amount of acetaminophen is reported to undergo deacetylation to the phase 1 metabolite paminophenol. www.indiandentalacademy.com
N-ACETYLCYSTEINE FOR ACETAMINOPHEN TOXICITY
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CARCENOGENSIS
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N-Hydroxylation of AAF
N-Hydroxylation of AAF is the first metabolic step towards the development of a carcinogenic agent www.indiandentalacademy.com
Further Metabolism of N-HydroxyAAF Produces Cancer
N-HydroxyAAF undergoes phase II metabolism to the ultimate carcingogen. The glucuronide pathway is also involved in carcinogenesis www.indiandentalacademy.com
CYP1A1 Converts Benzopyrene to a Carcinogen
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Aflatoxin is Metabolized to a Carcinogenic Agent
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FACTORS AFFECTING DRUG METABOLISM
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ENZYME INDUCTION
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CORRELATION BETWEEN SLEEPING TIME AND PLASMA T1/2 IN CHRONIC PENTOBARBITAL PRETREATED RABBITS
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Factors Affecting Drug Metabolism • Enzyme Induction - increased enzyme protein levels in the cell – Phenobarbital type induction by many drugs – Polycyclic hydrocarbon type induction by polycyclic hydrocarbons such as 3,4-benzopyrene and 3-methylcholanthrene
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AGE
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FACTORS AFFECTING DRUG METABOLISM
• Age – Neonates – Children – Elderly
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DIET
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FACTORS AFFECTING DRUG METABOLISM • Diet – Charcoal broiled foods (contain polycyclic hydrocarbons that increase certain enzyme protein in cells) – Grapefruit juice (the active component is the furancoumarin 6,7-dihydroxybergamottin which inhibits a certain a group of microsomal enzymes)
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GENETIC VARIATION
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Some Enzymes That Exhibit Genetic Variation – Pseudocholinesterase • typical enzyme • atypical enzyme – N-Acetyltransferase (isoniazid is a substrate) • fast acetylation • slow acetylation – Cytochrome P450 2D6 – Cytochrome P450 2C19 – TMPT -Thiomethylpurinetransferase – Dihydropyrimidine Dehydrogenase
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STATE OF HEALTH
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FACTORS AFFECTING DRUG METABOLISM
• State of health – Hepatitis – Liver cancer – Cardiac insufficiency – Uremia • degree of protein binding
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Changes In Drug Metabolism As A Consequence Of Hepatic Disease
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GENDER
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FACTORS AFFECTING DRUG METABOLISM • Gender – Most studies are performed in the rat. In general, male rats metabolize drugs faster than female rats
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DEGREE OF PROTEIN BINDING
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FACTORS AFFECTING DRUG METABOLISM
• Degree of protein binding – Conditions that displace bound drug from protein allows more of the drug to be accessible to the enzyme for which it serves as a substrate e.g. uremia, low plasma albumin
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SPECIES VARIATION
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FACTORS AFFECTING DRUG METABOLISM
• Species variation – Quantitative – Qualitative
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Factors Affecting Drug Metabolism
• Species variation – Human beings metabolize amphetamine by deamination; rats and dogs metabolize the drug by aromatic hydroxylation – Guinea pigs have very little sulfotransferase activity, humans have substantial activity – Guinea pigs do not N-hydroxylate substrates; mice, rabbits, dogs do – Hexobarbital is metabolized at different rates by different species
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SUBSTRATE COMPETITION
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Factors Affecting Drug Metabolism
• Substrate competition – Two or more drugs competing for the same enzyme can affect the metabolism of each other; the substrate for which the enzyme has the greater affinity would be preferentially metabolized
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