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713 311 PRINCIPLES OF VETERINARY PHARMACOLOGY

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Topic 4 Pharmacokinetics: Drug Metabolism 713 311 PRINCIPLES OF VETERINARY PHARMACOLOGY Dr. Korawuth Punareewattana Faculty of Veterinary Medicine, Khon Kaen University – PowerPoint PPT presentation

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Title: 713 311 PRINCIPLES OF VETERINARY PHARMACOLOGY


1
Pharmacokinetics Drug Metabolism
Topic 4
  • 713 311 PRINCIPLES OF VETERINARY PHARMACOLOGY
  • Dr. Korawuth Punareewattana

Faculty of Veterinary Medicine, Khon Kaen
University
2
Topic Contents
  • General concepts
  • Sites of metabolism
  • Enzyme cytochrome P-450
  • Phase I metabolism
  • Phase II metabolism
  • Factors that influence metabolism

3
Drug Elimination
  • Drug elimination consists of 2 processes
  • Drug Metabolism or Biotransformation
  • Drug Excretion

4
Drug Metabolism General concepts
  • Purpose
  • Elimination of drugs and foreign compounds
  • Major sites
  • Liver hepatocytes
  • Process in general
  • Parent drugs -gt metabolites
  • Lipid soluble -gt water soluble
  • (hard to excrete) -gt easier
  • Result
  • Inactive metabolite
  • Relatively non-toxic metabolite
  • Exception
  • sometime
  • Water soluble -gt lipid soluble
  • More toxic metabolite
  • Inactive prodrug -gt active drug

5
Drug Metabolism General concepts
  • In summary, drug metabolism will produce
    metabolites with altered properties
  • Activity of drugs can change in both ways
  • Inactive or less active most drugs
  • More active some drugs
  • Water solubility can also change in both ways
  • Incresed most processes
  • Decreased some processes

6
General Metabolic Pathways
  • Phase I metabolism
  • Processes of Functionalization
  • Phase II metabolism
  • Processes of Conjugation
  • Metabolism of a drug may not follow in order of
    these processes
  • It may go into phase I first then phase II
  • It may go into phase II without phase I
  • It may go into phase I twice then phase II

7
General Metabolic Pathways
  • Phase I reactions Functionalization
  • Oxidation
  • Reduction
  • Hydrolytic reactions
  • Purpose
  • Introduction of polar functional groups in a
    molecules
  • Hydroxyl groups
  • Carboxylate groups
  • Amino Groups
  • Thiol Groups
  • Increase a molecules polarity
  • May not produce metabolites for excretion
  • Does provide a site for phase II metabolism

8
General Metabolic Pathways
  • Phase II reactions Conjugation
  • Purpose
  • Introduce highly polar conjugates
  • Glucuronic acid
  • Sulfate
  • Glycine or other Amino Acids
  • Acetyl
  • Methyl
  • Glutathione
  • Site of attachment often introduced in Phase I
  • Hydroxyl
  • Carboxyl
  • Amino
  • Thiol
  • Conjugates are readily excreted in the urine
  • increased water solubility relative to the parent
    compound

9
An Example of Drug Metabolism
  • ?1-Tetrahydrocannabinol (?9)
  • Undergoes a series of metabolic steps prior to
    urine excretion

10
Sites of Metabolism
  • Liver
  • Primary site!
  • Highly perfused organ
  • Rich in enzymes
  • Acts on endogenous and exogenous compounds
  • First pass effect!
  • Extrahepatic metabolism sites
  • Intestinal wall
  • Sulfate conjugation
  • Esterase and lipases - important in prodrug
    metabolism
  • i.e. b-glucuronidase enzymes hydrolyze
    glucuronides for reabsorption
  • Enterohepatic recirculation
  • Bacterial flora
  • Reduction of Aromatic nitro and azo compounds
  • Lungs, kidney, placenta, brain, skin, adrenal
    glands
  • Limited ability and largely unknown

11
Enzyme Cytochrome P-450
  • Addition of an oxygen atom
  • Most common process (Liver)
  • General chemical equation is
  • RH NADPH O2 H ? ROH NADP H2O
  • Mixed function oxidases or monooxygenases located
    in the liver hepatocyte endoplasmic reticulum
  • Require NADH or NADPH and O2 as cofactors
  • Cytochrome P-450 or cytochrome b5 enzymes needed
  • Heme proteins
  • Iron containing porphyrin - binds O2
  • Works on a large number of diverse compounds

12
Cytochrome P-450 and Heme Protein
Cytochrome P-450
Heme protein
Cytochrome P-450, Hemoglobin, Myoglobin ALL
Heme Proteins!
13
Cytochrome P-450 Oxidative
  • Structural diversity due to
  • Nonspecificity
  • Isozymes - multiple forms of an enzyme
  • Enzymes are inducible by various chemicals
  • Exposure increases the rate of enzyme production
  • Enzymes isolated by disruption of the liver cells
  • Endoplasmic reticulum - microsomes when disrupted
  • Enzymes are membrane bound
  • Explains why lipophilic drugs are processed
  • Catalytic process ? heme binds O2

14
Cytochrome P-450 Cycle
15
Oxidative Reactions
  • Microsomal Enzymes
  • Aromatic hydroxylation
  • Epoxidation
  • Aliphatic hydroxylation
  • N-Dealkylation
  • N-Oxidation or N-Hydroxylation
  • O-Dealkylation
  • S-Dealkylation
  • S-Oxidation or Sulfoxidation
  • Desulfuration
  • Oxidative Dehalogenation
  • Nonmicrosomal Enzymes
  • Alcohol oxidation
  • Aldehyde oxidation
  • Amine oxidation or Oxidative Deamination
  • Monoamine oxidation
  • Diamine oxidation
  • Purine oxidation

16
Oxidative Reactions
17
Reductive Reactions
  • Occasionally convert carbonyl, nitro and azo
    groups
  • Carbonyl reductions generate alcohols
  • Nitro and Azo reductions generate amines
  • Alcohols and amines ?Phase II facilitate
    elimination
  • Reactions mediated by Aldo-Keto reductase enzymes

18
Reductive reactions cont
  • Microsomal
  • Nitro reduction
  • -gt amine
  • Nitroreductase
  • Azo reduction
  • -gt amine
  • Azoreductase
  • Nonmicrosomal
  • Aldehyde reduction
  • -gt alcohol
  • Aldoreductase
  • Ketone reduction
  • -gt alcohol
  • Ketoreductase

19
Nitro and Azo Reduction
NADPH dependent microsomal and nitro-reductase
enzymes Bacterial reductases play a role in
enterohepatic recirculation of nitro or azo
containing drugs
20
Hydrolysis of Esters and Amides
  • Catalyzed by widely distributed hydrolytic
    enzymes
  • Esters ? alcohols, phenols and carboxylic acids
  • Non-specific esterases (liver, kidney, and
    intestine)
  • Plasma pseudocholinesterases also participate
  • Amides ? amines and carboxylic acids
  • Liver microsomal amidases, esterases and
    deacylases
  • Hydrolysis of esters ? major metabolic pathway
    for ester drugs
  • Why? Ease of hydrolysis

21
Phase II Conjugation Reaction
  • Purpose Attach polar, ionizable small molecule
  • Result Sufficient water solubility for kidney
    excretion
  • Typically glucuronic acid, sulfate, amino acids
  • Glutathione (GSH)
  • conjugation occurs to combine with chemically
    reactive compounds to prevent their reacting with
    DNA, RNA and other proteins (Detoxification)
  • Other Phase II conjugations
  • Terminate or attenuate drug pharmacology
  • Methylation (attachment of a methyl group)
  • Acetylation (attachment of an acetyl group)
  • Phase II feature
  • Conjugating group is activated in the form of a
    coenzyme and involves a transferase enzyme

22
Glucuronic acid conjugation
  • Glucuronic acid attachment is the common
  • Derived from D-glucose
  • Carboxylic acid group pKa 3.2 so nearly 100
    ionized
  • Occur at hydroxyl groups, carboxylic acid
    groups, amino groups, thiol groups and rarely
    carbon atoms
  • UDP-glucuronyl transferase enzyme mediates this
    process
  • Liver, lung, kidney, skin, brain and intestine

23
Sulfate Conjugation
  • Occurs primarily with phenols
  • Rarely alcohols, aromatic amines, and N-hydroxyl
    compounds
  • Catalyzed by sulfotransferases
  • liver, kidney and intestine
  • Pool of sulfate available is limited
  • Leads to inactive water-soluble metabolites
  • Glucuronate conjugation often more competitive
    process

24
Amino Acid Conjugation
  • Amino acids are conjugated with carboxylic acids
  • Occurs in the mitochondria of liver and kidney
    cells
  • Conjugation in humans mostly glycine and
    L-glutamine
  • Conjugation is limited by amino acid pool
    available
  • Conjugates excreted in the urine via kidney
    (occasionally bile)
  • The carboxylic acid to be conjugated
  • Activated to form an active thioester from
    coenzyme A and ATP
  • Amino acid N-acyl-transferase enzymes mediate
    reaction

25
Glutathione (GSH) Conjugation
  • DETOXIFICATION of electrophiles!
  • Electrophilic chemicals cause
  • tissue necrosis
  • Carcinogenicity
  • Mutagenicity
  • Teratogenicity
  • The thiol (SH group) ties up potent electrophiles
  • GSH is in most tissues
  • GSH conjugates are NOT typically excreted
    further metabolized
  • Cyplasmic enzyme mediator glutathione
    S-transferase
  • Liver and kidney
  • No preactivation needed
  • Requirements sufficient electrophilicity

26
Glutathione (GSH) Conjugation
27
Acetylation
  • General concepts on Acetylation
  • Important route for drugs with primary amino
    groups
  • Process
  • Acetyl group is provided by Acetyl-CoA cofactor
    and
  • mediated by N-acetyltransferase enzymes
  • Primary site
  • hepatic reticuloendothelial cells
  • Also lung, spleen, gastric mucosa, RBC, and
    lymphocytes
  • Result
  • Acetylation does NOT increase water solubility
  • Generally, metabolites are nontoxic and inactive
  • Detoxification or termination of drug activity
  • Acetylation rarely leads to increased activity or
    toxicity

28
N-Acetylation of Drugs
29
Metabolism via Methylation
  • S-Adenosylmethionine (SAM) Methyltransferase
  • Key for biosynthesis of many compounds
  • Important in the inactivation of physiologically
    active biogenic amines
  • norepinephrine, dopamine, serotonin, histamine
  • Minor pathway in the metabolism of drugs

30
Metabolism via Methylation
  • Methylation does NOT increase water solubility
  • Most methylated products are inactive
  • Important methyl transferase enzymes involved
  • Catechol-O-methyl transferase (COMT)
  • Phenol-O-methyltransferase
  • Nonspecific N-methyl transferase
  • S-methyltransferase
  • Catechol-O-methyl transferase (COMT)
  • Widely distributed in tissues especially the
    liver and kidney
  • Responsible for inactivation of dopamine
    norepinephrine

31
Factors that influence metabolism
  • Age
  • older animals less efficient at metabolism
  • Sex
  • Linked to hormonal differences
  • Heredity
  • Genetic differences can influence amounts and
    efficiency of metabolic enzymes
  • Disease states
  • Liver, cardiac, kidney disease
  • Enzyme induction and Enzyme inhibition

32
Factors Genetic differences
  • Man vs. Monkey vs. Rabbit vs. Rat vs. Guinea pig
  • Differences can even be where in the drug
    metabolism occurs
  • Meta vs. para in aromatic rings and which of two
    aromatic rings
  • Example Cats
  • Cant conjugate phenols by glucuronic acid
  • Sulfate conjugate instead ? Aspirin BAD for
    kitty!
  • Example Pigs
  • Lack Sulfotransferase but very efficient
    glucoronic acid conjugation
  • Example Rabbits
  • Cottontail met. hexobarbitol 10X faster than New
    Zealand
  • Humans Genetic/hereditary differences account
    for huge differences seen in the rate of enzyme
    metabolism

33
Factors Enzyme Induction
  • Enzyme induction
  • Results from drug or chemical exposure
  • Very important source of drug-drug interactions
  • Caused by the increased rate of enzyme production
  • Often drugs can increase their own rate of
    metabolism
  • Compounds that enhance metabolism
  • Phenobarbital and other barbiturates,
  • glutethimide, phenylbutazone,
  • meprobamate, ethanol,
  • phenytoin, rifampin,
  • griseofulvin, carbamazepine

34
Factors Enzyme Inhibition
  • Enzyme inhibition and inhibition of metabolism
  • Leads to drug accumulation and toxicity
  • Mechanisms
  • Substrate competition
  • interference with protein synthesis
  • Interference with drug metabolizing enzymes
  • Hepatotoxicity leading to decreased metabolism
  • Others
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