Drug Metabolism Flashcards
body’s mechanism for processing, using, inactivating, and
eventually eliminating foreign substances, including drugs.
Metabolism i
recognizes the drug as a
foreign substance can break down or alter the chemical structure of drugs,
making them less active, or inert.
liver,
the blood, the lymph fluid, or any body tissue
role of these enzymes is to
degrade or modify the foreign structure, such that it can be more
easily excreted.
metabolic enzymes
defined as any
foreign substances or exogenous chemicals which the body does not recognize such as drugs, pollutants, others
Xenobiotics
once in the bloodstream, these molecules can ———– through other membranes and be distributed
effectively to reach various target organs to exert their pharmacological actions.
diffuse passively
for excretion
water soluble
for metabolism
lipophilic
Consequences of Drug Metabolism
May yield inactive metabolites (“detoxification of the drug”)
May retain similar activity
May produce metabolites with altered activity
Production of bioactivated metabolites
Hydrolysis of procaine to p- aminobenzoic acid & diethylethanolamine
(loss of anesthetic activity)
Oxidation of 6- mercaptopurine to 6- mercapturic acid
(loss of anticancer activity
Imipramine is demethylated
equally active antidepressant, desipramine
Acetohexamide is reduced
more active hypoglycemic, I- hydroxyhexamide
Codeine is demethylated
more active analgesic, morphine
Hydroxyzine (an antihistamine) can be metabolized
Cetirizine
antidepressant, Iproniazid is dealkylated
antitubercular drug, Isoniazid
retinoic acid (Vitamin A) is isomerized
anti- acne agent, isoretinoic acid
parent compounds
prodrugs
prodrug enalapril is hydrolyzed
enalaprilat
prodrug sulindac, a sulfoxide, is reduced
active sulfide (antibacterial)
antiparkinsonian levodopa (L- dopa) is decarboxylated
active dopamine
Sites of Drug Metabolism
Liver
Extrahepatic Metabolism
primary site of drug metabolism, functions to detoxify and facilitate excretion of xenobiotics (foreign
drugs or chemicals) by enzymatically converting lipid-soluble compounds to more water-soluble compounds.
liver
protect the organism against an accumulation of lipidsoluble exogenous and endogenous compounds by converting them to water-soluble metabolites which can be
easily excreted by the kidney are enymes located in
endoplasmic reticulum of liver cells
present in the liver are responsible for much of drug
metabolism
Cytochrome P450 enzyme species
affect the rate of
metabolism of a person.
liver cirrhosis, liver cancer, fatty liver disease, hepatitis,
drug biotransformation/ metabolism that takes place in tissues other than the liver
Extrahepatic Metabolism
Extrahepatic Metabolism
Plasma
Intestinal mucosa
Intestinal bacterial flora
Stomach
Nasal mucosa
Contains esterase enzymes which are responsible primarily for the hydrolysis of esters
Plasma
can activate a variety of prodrugs
, plasma esterases
Lipid- soluble drug passes through the intestinal mucosa which contains enzymes such as CYP 34A
Intestinal mucosa
Drug can be metabolized even before entering the blood
first pass effect
examples of drugs that easily undergo first- pass effect
imipramine
lignocaine
beta blockers
morphine
testosterone
Salbutamol
Cimetidine
Diazepam
Morphine
converts vitamin precursor to their active forms
convert certain substances to their toxic forms
Bacterial flora
enzyme that Intestinal flora produces which can also be responsible for metabolism
azoreductase
Intestinal bacterial flora secrete enzyme which can metabolize drugs
beta- glucuronidase
Has enzymes necessary for metabolism and has an acidic environment
Stomach
Provides a high level of CYP450 enzymes that can cause metabolism
Nasal mucosa
microsomal superfamily of
isoenzymes that catalyzes the oxidation of many drugs.
cytochrome P-450 (CYP450)
enzymes metabolize 90% of drugs.
CYP1A2 (2%), CYP2C9 (15%), CYP2C19 (15%), CYP2D6 (25%), CYP3A4
(60%), and CYP3A5 (2%)
true or false :
Drugs may be metabolized by only one CYP450 enzyme (e.g., metoprolol by CYP2D6) or by multiple enzymes (e.g.,
warfarin [Coumadin] by CYP1A2, CYP2D6, and CYP3A4)
true
With aging, the liver’s capacity for metabolism through the CYP450 enzyme system is reduced by ——-
because hepatic volume and blood flow are decreased.
≥ 30%
commonly due to impairments in the state of the enzymatic systems.
Qualitative changes
evolve in two directions:
Quantitative changes
the stimulation of enzymatic activity
(enzyme induction
the reverse, a reduction in enzyme activity
(enzyme inhibition
drug that causes change
precipitant drug
drug that undergoes change
object drug
block the metabolic activity of one or more CYP450 enzymes.
The extent to which an inhibitor affects the metabolism of a drug depends upon factors such as the dose and the
ability of the inhibitor to bind to the enzyme.
Inhibitors
increase CYP450 enzyme activity by increasing enzyme synthesis.
Unlike metabolic inhibition, there is usually a delay before enzyme activity increases, depending on the half-life of the
inducing drug
Inducers
These will slow down substrate drug metabolism and increase drug effect.
Enzyme inhibitor
These will speed up substrate drug metabolism and decrease drug effect.
Enzyme inducer
Phase I Metabolic Reactions
(Functionalization Reaction Phase)
Phase II Metabolic Reactions
(Conjugation Reaction Phase)
phase I reactions
oxidative processes (aromatic hydroxylation; aliphatic hydroxylation; N—, O—,
and S-dealkylation; N-hydroxylation; N-oxidation;
sulfoxidation; deamination; and dehalogenation),
reductive
(azoreduction, nitroreduction)
hydrolytic reactions.
purpose of these phase 1 metabolism reactions is to produce a compound with
increased polarity and
enhanced water solubility.
reactions undergone depend on;
nature of the available enzymes,
ii. the hydrocarbon skeleton of the drug and
iii. the functional groups present.
Phase I metabolic reactions are done by either of two ways:
Direct introduction of a functional polar group into the xenobiotic molecule; or
ii. Modifying or “unmasking” existing functionalities
first step of drug metabolism.
Oxidation
Conversion of a hydrogen to a hydroxyl group.
hydroxylation
Conversion of a hydroxyl group to a carbonyl group
R-C-OH ⇒ R-C=O (dehydrogenation)
Conversion of a carbonyl group to a carboxyl group.
- R-C=O ⇒ R-COOH (carboxylation)
R-C-NH2⇒R-C=O Conversion of an amino group to a carbonyl group
.(deamination)
R-CH3⇒ R-H
(demethylation)
enzymes of oxidation
mixed-function oxidases,
monoxygenases,
cytochrome P450 enzymes.
Reactions resulting in the addition of hydrogen and/or the removal of oxygen
Reduction
R-OH ⇒ R-H
(de-hydroxylation)
- R-C=O ⇒ R-C-OH
(hydrogenation)
(decarboxylation)
R-COOH ⇒ R-C=O
R-NO2⇒ R-NH2
(amination)
R-C-H ⇒ R-CH3
(methylation)
Enzymes involved in reduction reactions
reductases
In a reaction with water, a bond in the compound is broken, resulting in two compounds. At the same time the
water molecule splits in two, with a hydrogen transferring to one of the compounds and a hydroxide to the
other compound.
Hydrolysis
R-COO-R’ + H2O
R-COOH + R’-OH
R-CO-NH-R’ + H2O
R-CO-NH-R’ + H2O
e enzymes of hydrolysis reactions
esterases, peptidases, and amidases.
synthetic reactions where the product
or the metabolite from Phase I gets conjugated. This always produces a large, polar, metabolite that is readily excreted
from the body.
Conjugation reactions a
Phase II reactions
glucuronidation,
sulfation,
amino acid conjugation,
acetylation,
methylation or
glutathione conjugation to facilitate
elimination
Glucuronidation
Co- enzyme:
Transfer enzyme:
Co- enzyme: UDP-GA (Uridine diphosphateglucuronic acid)
Transfer enzyme: UDP (Uridine diphosphate) glucuronyl transferase
Glucuronidation Most Susceptible Functional Groups
-OH, -COOH, -NH2, -SO2NH2
Sulfation
Co-enzyme:
Trasnfer enzyme:
Co-enzyme: PAPS (3’-Phosphoadenosine-5’-
phosphosulfate)
Trasnfer enzyme: sulfotransferases
Sulfation Most Susceptible Functional Groups
-OH, -NH2, -SO2NH2, -NHOH
Glutathione Conjugation
Transfer enzyme
Transfer enzyme: Glutathione-S-transferase
Amino acid Conjugation
Co-enzyme
Transfer enzyme
Co-enzyme: acyl-CoA synthetase
Transfer enzyme: N-acetyltransferase
Acetylation
Co-enzyme
Transfer enzyme
Co-enzyme: acyl-CoA synthetase
Transfer enzyme: N-acetyltransferase
Methylation
Transfer enzyme:
Transfer enzyme: methyltransferases
Glutathione Most Susceptible Functional Groups
Alkyl halides, alkyl nitrates, epoxides,
lactones, electrophilic centers
Amino acid Conjugation Most Susceptible Functional Groups
-COOH, -NH2
Acetylation Co-enzyme Most Susceptible Functional Groups
-OH, -NH2, -SO2NH2, -NHOH, -NHNH2
Methylation Most Susceptible Functional Groups
-OH, NH2, -SH
Active metabolite of the prodrug simvastatin
B-hydroxy acid metabolite
Active metabolite of the prodrug Capacitabine
Fluorouracil
Active metabolite of the prodrug Ramipril
Ramiprilat
Active metabolite of the prodrug of Terfenadine
Fexofenadine
Allopurinol
Oxypurinol
Active metabolite of the prodrug of Bambuterol
Terbutaline
Nabumetone
6 methoxy-2-naphthylacetic acid
