Metabolic Changes Of Drugs Flashcards
the process by which the drug is chemically converted in the body to a metabolite
drug metabolism
-formation of Polar compounds
enhance the elimination of xenobiotics
formation of inactive/relatively nontoxic compounds
detoxification
main site of drug metabolism
Liver
lowers the bioavailability
first pass effect
-CYP3A4
-P-glycoprotein
-bacterial flora
Intestinal mucosa
drug are metabolized in the liver before they are distributed to the rest of the body
-isoproterenol
-lidocaine
-morphine
-nitroglycerin
-pentazocin
-propoxyphene
-propanolol
first pass effect
intentionally designed to improve drug stability, increase systemic drug absorption, or to prolong the duration of activity
Prodrug (inactive)
rapid metabolism of an orally administered drug before reaching the general circulation
first pass effect or presystemic elimination
kinds of metabolite
-active metabolite
-parent drug or in/active metabolite
-toxic metabolite
the most important enzyme system affecting drug metabolism
CYP450
enzyme system
are known as poor metabolizers
5-14% of Caucasians
0-5% Africans
0-1% of Asians
lack CYP2D6 activity
Superfamily of enzymes:
-drug metabolism
-bioactivation
-breakdown of xenobiotics
-turn drugs into soluble molecule so that it can be excreted
CPY450 enzymes
any foreign chemical substance found in an organism that is not normally naturally produced by or expected to be present in that organism
Xenobiotics
-Oxidative biotransformation
-mixed function oxidases or monooxygenases
-responsible for transferring an oxygen atom to the substrate R-H
-Heme proteins
*protoporphyrin IX
*proprotein
-substrate nonspecific
Cytochrome P450 enzymes
CYP arabic numbers: CYP1
family:
must have more than 40% identical amino acid sequence
capital letter after the arabic number CYP1A
subfamily:
must have more than 55% identical amino acid sequence
arabic number after capital letter CYP1A1
individual enzyme in the subfamily
identity of amino acid sequences can exceed 90%
1A1
-Caffeine
-Testosterone
-R-Warfarin
1A2
-Acetaminophen
-Caffeine
-Phenacetin
-R-Warfarin
2A6
-17beta-Estradiol
-Testosterone
2B6
-Cyclophosphamide
-Erythromycin
-Testosterone
2C family
-Acetaminophen
-Tolbutamide (2C9)
-Hexobarbital
-S-Warfarin
-Phenytoin
-Testosterone
-R-Warfarin
-Zidovudine
2E1
Acetaminophen
Caffeine
Chlorzoxazone
Halothane
2D6
Acetaminophen
Codeine
Debrisoquine
3A4
Acetaminophen
Caffeine
Carbamazepine
Codeine
Cortisol
Erythromycin
Cyclophosphamide
S & R -Warfarin
Phenytoin
Testosterone
Halothane
Zidovudine
metabolic pathways
phase 1
phase 2
Phase 1
or functionalization reactions
-oxidation:
* aromatic moieties
* olefins
* benzylic, allylic carbon atoms, & carbon atoms alpha to carbons & imines
* at aliphatic & alicyclic carbon atoms
* of alcohols & aldehydes
* other miscellaneous oxidative reactions
oxidation involving carbon-heteroatom systems:
-carbon-nitrogen systems aliphatic & aromatic amines include:
N-dealkylation
Oxidative deamination
N-oxide formation
N-hydroxylation
-carbon-oxygen system
O-dealkylation
-carbon-sulfur system
S-dealkylation
S-oxidation
desulfuration
Phase 1 or functionalization
-oxidation
-reduction
-hydrolysis
phase 1 reduction
-reduction of aldehydes & ketones
-reduction of nitro & azo compounds
-miscellaneous reductive reactions
phase 1 hydrolytic reactions
-hydrolysis of esters & amides
-hydration of epoxides & arene oxides by epoxide hydrase
phase 2 or conjugation reaction
-glucoronic acid conjugation
-sulfate conjugation
-conjugation with glycine, glutamine & other amino acids
-glutathione or mercapturic acid conjugation
-acetylation
-methylation
phase 1 metabolism
-functionalization reactions
-introduction of functional POLAR group (OH, COOH, NH2, SH)
phase 1 metabolism may be achieved by
-Direct introduction of functional group
-modifying or unmasking existing functional groups
modifying or unmasking
Oxidation
Reduction
Hydrolysis
paracetamol goes to phase 2 because
if phase 1, will produce toxic metabolites
a chemical reaction in which a hydroxyl group (-OH) is added to a nitrogen atom
N-hydroxylation
a chemical process in which an alkyl group (such as a methyl, ethyl, or other alkyl chain) is removed from a nitrogen atom
N-dealkylation
involves the removal of an amine group (-NH₂) from a compound, typically converting the compound into a keto acid and releasing ammonia (NH₃). The nitrogen is oxidized, and the process is catalyzed by specific enzymes, often involving cytochrome P450 enzymes or monoamine oxidase (MAO).
Oxidative deamination
process where an oxygen atom is added to the nitrogen atom in amine-containing compounds or heterocyclic nitrogen-containing molecules, forming an N-oxide. This reaction, catalyzed by cytochrome P450 enzymes, increases the polarity of the compound, facilitating its excretion through urinary elimination.
Phase 1 Metabolism N-Oxide formation
Phase 1 metabolism carbon hydroxylation
-oxidative reaction where a hydroxyl group (–OH) is added to a carbon atom in the molecule.
-increases the hydrophilicity of the compound, making it more water-soluble and easier for the body to eliminate.
oxidative process in which an alkyl group (such as methyl, ethyl, or larger alkyl chains) is cleaved from an oxygen atom in an ether linkage. The result of this process is the formation of a hydroxy metabolite (i.e., the alkyl group is replaced with a hydroxyl group), making the compound more polar and more easily excreted by the body
O-Dealkylation in Phase 1 Metabolism
metabolic reaction in which an alkyl group (such as a methyl or ethyl group) is removed from a sulfur atom (–S) that is part of a thioether (–S–alkyl) group.
S-Dealkylation in Phase 1 Metabolism
metabolic reaction where a sulfur atom (–S) in a thioether or thiol group is oxidized, typically converting the sulfur atom into a more oxidized form such as a sulfoxide (–SO) or sulfone (–SO₂).
S-Oxidation in Phase 1 Metabolism
-metabolic reaction in which a sulfur atom is removed from a sulfur-containing compound (such as a thiol or thioether) during metabolism
- primarily catalyzed by cytochrome P450 enzymes (CYP450), although other enzymes, like flavin-containing monooxygenases (FMOs), can also be involved in desulfuration reactions
Desulfuration in Phase 1 Metabolism
important in detoxification, particularly for compounds that might not be efficiently processed by cytochrome P450 enzymes
Flavin-containing monooxygenases (FMOs)
plays a significant role, particularly in the oxidative deamination of biogenic amines (such as neurotransmitters) and certain xenobiotics (foreign substances). This enzyme catalyzes the oxidation of amines, which is crucial for detoxification and inactivation of various compounds in the body.
monoamine oxidase (MAO)
involved in the oxidative metabolism of alcohol by converting alcohols to aldehydes
Alcohol Dehydrogenase (ADH)
inhibits the enzyme aldehyde dehydrogenase (ALDH), which is a key enzyme in the metabolism of alcohol.
disulfiram
hydrolysis of esters
esterases
hydrolysis of amines
peptidases
- Attach small, polar* and ionizable endogenous compounds
- Glucuronic acid, sulfate, glycine and other amino acids
- Eliminated in the urine
- Catalyzed by transferase enzymes
- Conjugated metabolites are generally devoid of pharmacological activity and
toxicity
Conjugation
the most common conjugative pathway in drug metabolism
Glucuronidation
Glucuronidation is the most common conjugative pathway in drug metabolism for several reasons:
- readily available supply of D-glucuronic acid (derived from D-glucose);
- numerous functional groups that can combine enzymatically with glucuronic acid; and
- the glucuronyl moiety when attached to xenobiotic substrates, greatly increases the water solubility of the
conjugated product.
play a critical role in detoxification by catalyzing the transfer of glucuronic acid (a sugar molecule) to a variety of substrates, including drugs, toxins, and endogenous compounds, making them more water-soluble and easier for the body to excrete, primarily via urine or bile.
UDP-glucuronosyltransferase
UDP
Uridine Diphosphate
direct attachment of glucoronide
glucoronidation
Sulfate conjugation
-phase 2 metabolic reaction where a sulfonate group (−SO₃) is transferred to a substrate, typically a hydroxyl group, amine, or carboxyl group
Sulfonation
Phase II Reactions: Sulfation
Cofactor:
3-Phosphoadenosine-5- phosphosulfate (PAPS)
Enzyme: Sulfotransferase
- Conjugation of xenobiotics with sulfate occurs primarily with phenols and, occasionally, with alcohols, aromatic amines, and
N-hydroxy compounds.
Sulfonation or Sulfate Conjugation
The body uses a significant portion of the sulphate pool to conjugate
numerous endogenous compounds such as
steroids,
heparin,
chondroitin,
catecholamines, and thyroxine
The sulfate conjugation process involves activation of inorganic sulfate
to the coenzyme
3-phosphoadenosine- 5-phosphosulfate (PAPS)
NOT yet fully developed in neonates and
children.
Glucoronidation
results from the inability of infants to conjugate
chloramphenicol with glucuronic acid
Gray baby syndrome
results from the inability of newborns to conjugate
bilirubin with glucuronic acid
Neonatal hyperbilirubinemia (or kernicterus)
amino acids used to conjugate carboxylic acids, particularly aromatic acids and arylalkyl acids
glycine and glutamine
Glycine conjugation is common to
most mammals
glutamine conjugation appears to be
confined mainly to
humans & other primates
phase 2 metabolic reaction in which an amino acid is added to a substrate (typically a drug, xenobiotic, or endogenous molecule) to make it more water-soluble and facilitate its excretion from the body
Amino acid conjugation
it generally involves the formation of a peptide bond b/w the amino acid & the substrate
Amino Acid Conjugation
enzymes involved in amino acid conjugation
acyltransferase
Glycine Conjugation with Benzoic Acid forms
Hippuric Acid
Amino acid conjugation of salicylic acid primarily involves the conjugation of glycine to form
salicyluric acid
- Takes place in most cells, especially liver and kidney
- Important in detoxifying potentially dangerous environmental toxins or
electrophilic alkylating agents
Glutathione Conjugation
Xenobiotics conjugated with GSH usually are not excreted as such, but undergo further biotransformation to give S-substituted N-acetylcysteine
products called
mercapturic acids
Glutathione (GSH) is a tripeptide
Cysteine
Glycine
Glutamic Acid
Enzyme Involved in GSH conjugation
Glutathione S-transferase
Main function: terminate pharmacological activity and detoxification
Acetylation
- Individuals are classified as having either slow or rapid acetylator phenotypes.
- This variation is genetic and is caused mainly by differences in N-
acetyltransferase activity.
Acetylation polymorphism
Rapid Acetylators
eskimos and asians
slow acetylators
egyptians & some western european
a common phase 2 metabolic reaction where an acetyl group (CH₃CO–) is transferred to a substrate, often modifying its properties such as solubility, activity, and toxicity
Acetylation
The primary enzyme responsible for acetylation is
acetyltransferase, with the most common example being N-acetyltransferase (NAT)
Important in the biosynthesis of many endogenous compounds (e.g.,
epinephrine and melatonin) and in the inactivation of numerous
physiologically active biogenic amines (e.g., norepinephrine, dopamine,
serotonin, and histamine)
Methylation
coenzyme involved in methylation reactions
S- adenosylmethionine (SAM)
enzyme involved in the methylation of catechol (dopamine, norepinephrine)
COMT (Catechol-O-methyltransferase)
Substrates for COMT
Norepinephrine to Normetanephrine
Dopamine to 3-methoxytyramine
Factors affecting biotransformation
-Diseases
-Race
-Age
-Sex
-Species
-Clinical or psychological condition
-other drug administration (induction or inhibition)
-food
-first pass (pre-systemic) metabolism
other factors affecting biotransformation
-pharmacogenomics
-caucasians are slow acetylators
-drug-drug interaction
enzyme inducers
ppprccss
Phenobarbital
Phenytoin
Primidone
Rifampicin
Carbamazepine
Chronic Alcoholism
St. John’s wort
Smoking
enzyme inhibitors
medviicccckga
Metronidazole
Erythromycin, Enoxacin
Disulfiram, Diltiazem,
Diphenhydramine
Isoniazid, Indinavir
Chloramphenicol, Cimetidine,
Ciprofloxacin,
Clarithromycin
Ketoconazole
Grapefruit juice
Acute Alcoholism
due to prolonged use, high concentration of drug, genetic polymorphism, interaction, etc
toxication or metabolic activation
major route in metabolism of paracetamol in children
Sulfation
major route in metabolism of paracetamol in adults
glucoronidation
toxic metabolite formed from acetaminophen
NAPQI
N-acetyl-para-benzo-quinone imine
