BIOTRANSFORMATION Flashcards

1
Q

WHY DRUG TRANSFORMATION NECESSARY?

A

• Pharmacologically active organic molecules tend to
be lipophilic and they remain unionized or only
partially ionized at physiologic pH; these are readily
reabsorbed from the glomerular filtrate in the
nephron.
• Certain lipophilic compounds are often strongly
bound to plasma proteins and may not be readily
filtered at the glomerulus.
• Metabolic products are often less
pharmacodynamically active than the parent drug
and may even be inactive.
• However, some biotransformation products have
enhanced activity or toxic properties.
• Therefore, lipid-soluble agents are first metabolized
into more polar (hydrophilic) substances in the liver
via two general sets of reactions, called phase 1
and phase 2.

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2
Q

Phase 1 reactions

A

usually convert the parent drug to
a more polar metabolite by introducing or
unmasking a functional group (–OH, –NH2, –SH)

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3
Q

If phase 1 metabolites are sufficiently polar

A

they may be readily excreted.

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4
Q

However, many phase 1 products are not eliminated
rapidly and undergo a subsequent reaction in which
an endogenous substrate such as

A

glucuronic acid,
sulfuric acid, acetic acid, or an amino acid combines
with the newly incorporated functional group to form
a highly polar conjugate.

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5
Q

hydrazide moiety of isoniazid is

known to form an

A

N-acetyl conjugate in a phase 2

reaction

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6
Q

Thus, phase 2 reactions may actually precede

A

phase 1 reactions.

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7
Q

Phase 2 reaction,

A

this facilitates elimination of the

drug and it can be in the form of conjugation, sulfation, acetylation or methylation.

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8
Q

• Phase 1 involves

A

Oxidation-Reduction (REDOX

Reaction)

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9
Q

Phase 2 involves

A

transferases or conjugation

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10
Q

This conjugation reaction usually requires the
substrate to have Oxygen, Nitrogen or Sulfur that
serve as acceptor sites for the hydrophilic moiety,
such as glutathione, glucuronic acid, sulfate or
acetyl

A

: a drug may undergo Phase 1 via
oxidation, addition of Oxygen. And that Oxygen
would serve as a substrate, where in this component
would be added in replace to the functional group.

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11
Q

What is the importance of biotransformation?

A

For elimination

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12
Q

What will happen if the drug is not metabolized?

A

Increase risk for toxicity because the drug
remains in the blood. So, after absorption, it will
be distributed and then metabolize for it to be
excreted.

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13
Q

Phenytoin is highly lipophilic, via Phase 1 reaction

acted upon by

A

CYT p450

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14
Q

Phenoytin Reaction

A

converted, and then addition of a functional
group, forming 4-hydroxy-phenytoin. Then after
Phase 1, this phenytoin would be slightly soluble in
water. It would further undergo Phase 2 reaction by
glucuronidation, addition of UGT, where in your
hydroxyl group serves as the substrate. This
metabolite is more water soluble and it can be easily
excreted in the kidney

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15
Q

WHERE DO DRUG BIOTRANSFORMATION

OCCUR?

A

Liver is the principal organ of drug

metabolism.

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16
Q

If phase 1 metabolites are sufficiently polar

A

they

may be readily excreted.

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17
Q

The small intestine plays an important role in metabolism since drug that are orally administered absorbed by the GUT and taken to the liver through
the portal vein

A

FPM

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18
Q

xenobiotic metabolizing enzyme

A

located
in the epithelial cells of the GI are also responsible
for the initial metabolic process of most oral
medication. So, this should be consider as the initial
site of drug metabolism

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19
Q

Drugs that undergo Substantial FPM

A
Asprin
Glyceral Trinitrate
Isosorbide dinitrate
Levodopa
Lidocaine
Metoprolol
Morphine
Propanolol
Salbutamol
Verapmil
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20
Q

are more extensively

metabolized in the intestine than in the liver

A

clonazepam, chlorpromazine, cyclosporine

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21
Q
undergo significant (~50%)
intestinal metabolism.
A

midazolam

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22
Q

First-pass effects may limit the bioavailability of
orally administered drugs (eg., lidocaine) so greatly
that

A

alternative routes of administration must be used to achieve therapeutically effective blood levels.

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23
Q

Furthermore, the lower gut harbors intestinal microorganisms that are capable of many

A

biotransformation reactions

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24
Q

Drugs may be metabolized by gastric acid

A

Penicillin

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25
Digestive enzumes metabolism
Polypeptides like insulin
26
enzymes in the wall of the | intestine
sympathomimetic catecholamines
27
RER are used for
protein | synthesis
28
SER are rich in | enzymes responsible for
oxidative drug metabolism and this is where your Cytochrome P450 enzyme or your mixed function oxidases are located.
29
PHASE 1 REACTIONS
: Oxygenase, addition of functional group, they can be accomplished by Cytochrome P450, FMO as well as epoxide hydroxylases.
30
phase 1 reaction are three enzymes
CytP450
31
In this oxidation reaction process, 2 microsomal | enzymes play a key role
First is your NADPH (nicotinamide adenine dinucleotide phosphate dehydrogenase) and 1 mole of this enzyme donates an electron to the flavoprotein P450 reductase. (contains 1 mole of FMN/Flavin mononucleotide and FAD/Flavin adenine dinucleotide).
32
The second microsomal enzyme is a hemoprotein | called your Cytochrome P450
which serves as your terminal oxidase. So, in its reduced form, in ferrous form (Fe²⁺) it binds carbon monoxide to give a complex that absorb light at approximately at 450nm. Hence, the name Cytochrome P450.
33
Nomenclature:
o The family name is indicated by the Arabic number that follows CYP, and the capital letter designates the subfamily, for example, CYP3A o A second number indicates the specific isozyme, as in CYP3A4
34
CYP3A4
Responsible for the metabolism of over 50% of the prescription drugs metabolized by the liver.
35
most common | drugs are
CYP1A2, 2A6, 2B6, 2C9, 2D6, 2E1, | 3A4.
36
g efficacy and there is adverse effect. For example, CYP2D6 has mentioned to exhibit
. So, if the is genetic polymorphism, the risk for drug-drug interaction also increases.
37
PHASE 1 REACTIONS: CYTOCHROME P450 (CYP) | ENZYME INDUCTION
This results in increased biotransformation of drugs and can lead to significant decreases in plasma concentrations of drugs metabolized by these CYP isozymes, with concurrent loss of pharmacologic effect
38
f drug red is metabolized by CYP3A4 and the drug yellow is also metabolized by CYP3A4. If drug yellow induced the metabolism of drug red, will there be an increase or decrease in the metabolism of the drug red?
Increase in the metabolism of drug red.
39
What would happen to the effect of drug | red?
Decrease in effect. Since faster metabolism of drug red. Drug yellow induces or accelerates the metabolism of drug red.
40
Question: If you are given or prescribed with 2 drugs and 1 drug induces the metabolism of the other drug. How would you now address the situation to obtain the desirable effect? Would you increase the dosage of drug yellow or increase the dosage of drug red? Or decrease dosage of drug yellow or decrease dosage of drug red?
You can increase the dose of drug red or decrease yellow or better is to change drug yellow
41
Maximal effects usually occur after
7 to 14 days and would require equal or longer time to dissipate after the enzyme inducer is stopped
42
CYTOCHROME P450 (CYP) ENZYME INDUCTION
When a drug such as atorvastatin (used to decrease your blood cholesterol; mechanism: HMG-COA reductase inhibitor). So, your atorvastatin here serves as the ligand, it enters the cell and it can bind to nuclear receptor such as your PXR, then PXR forms a complex with your RXR (Retinoid X Receptor), and it binds to DNA upstream of target genes. So, this binding would recruit your coactivator which binds to your TATA box and activates transcription by RNA polymerase.
43
Aromatic HC
binds the ligand-binding domain of soluble protein, AROMATIC HC RECEPTOR (AHR) ● Complex is transported to the nucleus by AHR nuclear translocator (PROMOTES GENE TRANSCRIPTION
44
Aryl Hydrocarbon AHR
Omeparazole
45
CAR (Androstane)
Phenobarbital
46
PXR
Rifapmin
47
FXR
Bile acid
48
PPAR
Fibrates
49
RAR
All trans retinoic acid
50
RXR
9-cis Retinoic acid
51
Induction
it would accelerate the metabolism by inducing the synthesis of your Cytochrome P450, reducing the effect of the ligand.
52
The most common form of inhibition
through | competition for the same isozyme.
53
drug red and then drug yellow, wherein they are metabolized by the same CYP450, but drug yellow is an inhibitor. So, what would be the effect on the metabolism of your drug red
? It would | be enzyme inhibition.
54
if there is decrease in the metabolism of drug red, what would happen to its biologic effect?
An increase in biological effect, It can increase the risk for toxicity.
55
How would you address the problem in enzyme | inhibition wherein there is increased risk for toxicity?
Decrease the dose of drug red or you can change drug yellow, as we are preventing drug-drug interaction, to prevent toxicity
56
most common is your CYP3A4
50% are metabolized by it
57
CYP1A2, has
has substrate of acetaminophen, with inducers of lansoprazole, primidone, rifampin. Acetaminophen effect is not that significant unless you give a toxic dose.
58
carbamazepine and rifampin wherein | they are metabolized by your CYP2C8
if both drugs are given where rifampin is an inducer, so meaning rifampin would facilitate or accelerate the metabolism of your carbamazepine, decreasing its effect but if carbamazepine is given together with your gemfibrozil (inhibitor), metabolized by the same CYP, it would inhibit the metabolism of carbamazepine, therefore the effect of carbamazepine is increased when you give it concomitantly with gemfibrozil.
59
● 16-year-old patient sought to consult due to a cough of 2 weeks duration. ● He is known asthmatic. On PE, RR 45 with subcostal retractions and wheezes and rales on both lungs. With an impression of atypical pneumonia and Bronchial asthma in acute exacerbation, Prednisone and Salbutamol nebulization was given. ● Which of the following antimicrobials would be of benefit for this patient? a) Amoxicillin b) Cefuroxime c) Azithromycin d) Clarithromycin
C Azithromycin Drugs given were Prednisone and salbutamol, Case is chlamydia Azithromycin and Clarithromycin have coverage for atypical microorganisms such as mycoplasma and chlamydia. Prednisone is metabolized by CYP3A4 then clarithromycin is an inhibitor, considering drug-drug interaction, prednisone concentration in the body would be increased therefore increasing its effect and toxicity. So, among these drugs, better to give azithromycin as it has no drug interaction with prednisone nor salbutamol.
60
PHASE 2 REACTIONS
Parent drugs or their phase 1 metabolites that contain suitable chemical groups often undergo coupling or conjugation reactions with an endogenous substance to yield drug conjugates. • These reactions are synthetic, anabolic and involving conjugations. Phase 2 reactions also occurred in the liver. So, if your phase 1 is adding your functional group which serves as a substrate where in the Phase 2 reactions, you conjugate the drug or you couple it to yield drug conjugate.
61
most reactions are via
UGT make table of phase 1 and phase 2 rxn tables.
62
GLUCURONIDATION
Glucuronide formation involves the formation of a high-energy phosphate compound, uridine diphosphate glucuronic acid (UDPGA) → from which glucuronic acid is transferred to an electron-rich atom (N, O or S) on the substrate, forming an amide, ester or thiol bond.
63
UDP-glucuronyl | transferase.
This is an example of | glucuronidation reaction, via the addition of glucuronide
64
SULFATION
Sulfotransferases (SULTs) are cytosolic and conjugate sulfate derived from 3ʹ-phosphoadenosine5ʹ-phosphosulfate (PAPS) to the hydroxyl and, less frequently, amine groups of aromatic and aliphatic compounds. • SULTs play an important role in normal human homeostasis.
65
SULT2B1b
predominant form expressed in skin, | carrying out the catalysis of cholesterol.
66
SULT2A1
highly expressed in the fetal adrenal | gland.
67
SULT1A3 is
highly selective for catecholamines
68
• SULT1E1
estrogen.
69
GLUTATHIONE CONJUGATION
• The substrate in the reaction is a tripeptide glutathione which is synthesized from glutamic acid, cysteine, and glycine
70
Glutathione exist in cell as oxidized or reduced form | and the ratio is critica
maintaining cellular | environment in reduced state.
71
The glutathione-S-transferases (GSTs) catalyze the | transfer of glutathione to reactive electrophile
a function that serves to protect cellular macromolecules from interacting with electrophiles that contain electrophilic heteroatoms (-O, -N, and -S) and in turn protects the cellular environment from damage.
72
ACETYLATION
There are two genes for N-acetylation, NAT1 and NAT2
73
Example of a drug that undergoes N-acetylation
Isoniazid
74
If the subject or the patient has a slow acetylator | gene,
decrease metabolism of isoniazid by Nacetylation, thereby increase in the risk for adverse effect.
75
hydralazine
which contains the hydrazine group, undergoes N-acetylation, so if there is genetic polymorphism, and the patient is a slow acetylator type, and then you give hydralazine, which is used in treating hypertension, it can aggravate hypotension, tachycardia, and headache. But if the patient is a rapid acetylator, there is decreased in the effect of hydralazine as well as decreased side effect
76
Acetaminophen, an analgesic antipyretic drug, is | quite safe in therapeutic doses (1.2 g/d for an adult).
It normally undergoes glucuronidation and sulfation to the corresponding conjugates, which together make up 95% of the total excreted metabolites. The alternative P450-dependent GSH conjugation pathway accounts for the remaining 5%. When acetaminophen intake far exceeds therapeutic doses
77
Acetaminophen metabolism via Phase 2, 95% would | undergo
glucuronidation as well as sulfation. Only 5% is cytochrome P450 dependent GSH conjugate pathway? At therapeutic dose, acetaminophen would undergo this pathway and sulfation pathway
78
there is toxic dose for acetaminophen
toxic dose is a single injection of 7.5-10g or acute injection of 12g of acetaminophen, and for children ingestion of more that 150mg/kg, so glucuronidation reaction as well as sulfation reaction would be saturated, so they cannot afford the excess acetaminophen, there will be increase in the metabolism via cytochrome P450 enzyme.
79
treatment of acetaminophen toxicity
NAC, within 6-8 hours
80
GENETIC FACTORS
A true genetic polymorphism is defined as the occurrence of a variant allele of a gene at a population frequency of ≥ 1%, resulting in altered expression or functional activity of the gene product, or both
81
PHASE 1 ENZYME POLYMORPHISM
It involves FOM, hydroxylases, as well as | cytochrome P450.
82
Poor Metabolizer (PM)
``` faulty expression of the P450 protein due to either defective mRNA splicing or protein folding, resulting in little or no isoform-catalyzed drug metabolism. o meaning, the Phase 1 reaction is prolonged secondary to messenger RNA defect ```
83
Ultrarapid Metabolizer (UM)
``` o most common in Ethiopians and Saudi Arabians, populations that display it in up to one-third of individuals o require twofold to threefold higher daily doses o has fast drug metabolism o for fast metabolizers or ultrarapid metabolizers, to attain the therapeutic the effect, increase the dose by two times or three times ```
84
PHASE 2 ENZYME POLYMORPHISM
``` . PHASE 2 ENZYME POLYMORPHISM • The problem can be in conjugation, acetylation, sulfation, methylation • The commonly described is your acetylation enzyme polymorphism Phase 2. • So, they can be categorized as Slow Acetylator or Rapid Acetylator ```
85
SLOW ACETYLATOR PHENOTYPE
The defect in slow acetylators (of isoniazid and similar amines) appears to be caused by the synthesis of less of the NAT2 enzyme rather than of an abnormal form of it. • For Slow Acetylator Phenotype, mostly, their polymorphism affects NAT2 than NAT1. • 50% of blacks and whites in the USA, more frequently in Europeans living in high northern latitudes • Associated with a higher incidence of isoniazidinduced peripheral neuritis, drug-induced autoimmune disorders, and bicyclic aromatic amineinduced bladder cancer
86
Isoniazid is metabolized by a Phase II through Nacetylation. If the patient has the slow acetylator phenotype, metabolism of your isoniazid is
Slow
87
if there is an increase in the effect of Isoniazid, it can increase the adverse effects of Isoniazid such as
Peripheral Neuritis
88
Hydralazine would also undergo acetylation? If the patient has slow acetylator phenotype, it can aggravate the hypotensive effect as well as
tachycardia caused by your Hydralazine
89
Sulfonamide, which also undergoes acetylation. | It can aggravate the side effect of your Sulfonamide
hypersensitivity reaction leading to druginduced autoimmune disorder.
90
For Slow Acetylators,
f the drug is really needed, you can decrease the dosage or prolong the frequency of interval of administration of the drug to reduce the risk for adverse effects.
91
RAPID ACETYLATOR PHENOTYPE
Isoniazid, so decreased biologic effects of Isoniazid. To achieve the therapeutic effects of Isoniazid to a patient classified as Rapid Acetylator, you increase the dosage.
92
Charcoal-broiled foods ®
induce CYP1A enzymes
93
Grapefruit juice ®
inhibit the CYP3A metabolism of | co-administered drug substrate
94
Cigarette smoker ®
metabolize some drugs more rapidly than nonsmokers because of enzyme induction
95
Industrial workers exposed to some pesticides ®
metabolize drug more rapidly
96
Extremes of ages
increased susceptibility to | pharmacologic or toxic activity of drugs because of the decrease in metabolism
97
eonates and children have limited | ability for xenobiotic biotransformation because:
At birth, the level of your cytochrome P450 is diminished, and then as their age increases, the level of cytochrome P450 also increases. However, the effect and biologic activity of cytochrome P450 are not that mature.
98
Slower metabolism
Reduced activity of metabolic enzymes o Reduced availability of essential endogenous cofactors
99
DRUG-DRUG INTERACTIONS DURING | METABOLISM
Overlapping substrate specificities by the CYPs is one of the underlying reasons for the predominance of drug-drug interactions. • So, when 2 co-administered drugs are both metabolized by your single cytochrome P450, they compete to bind to the enzyme active site. So, this drug can either induce or inhibit the metabolism of the same drug. So, this refers to your drug-drug interaction leading to the cause of your adverse effect.
100
An inducer may enhance not only the metabolism of the other drug but also its own metabolism
Atrovastatin
101
Atorvastatin itself would induce the | synthesis of the cytochrome P450 enzyme
CYP3A4
102
Cimetidine (H2 blocker). Which is prescribed for Acid Peptic Disease. So, if Cimetidine is given concomitantly with Warfarin (anti-coagulant). Since Cimetidine is an enzyme inhibitor, there will be decreased metabolism of Warfarin. S
So, there will be an increase in effect of Warfarin, meaning, an increased risk for bleeding.
103
INTERACTIONS BETWEEN DRUGS & | ENDOGENOUS COMPOUNDS
steep dose-response curve or a narrow margin of safety, potentiation of its therapeutic and toxic effects may result
104
. DISEASES AFFECTING DRUG METABOLISM
• Liver. Acute or chronic diseases that affect liver architecture or function markedly affect hepatic metabolism of some drugs. Isn’t it the primary organ for biotransformation is your liver? o Alcoholic hepatitis o Active or inactive hepatitis o Biliary cirrhosis o Acute viral or drug-induced hepatitis o Impair hepatic drug-metabolizing enzymes (microsomal oxid