4) Biotransformations Flashcards
(78 cards)
1
Q
Primary purpose of drug metabolism
A
- Render lipid soluble and non-polar compounds to water soluble and polar compounds for easy excretion
2
Q
Only water-soluble substances undergo
A
- Excretion
3
Q
Lipid-soluble substances are
A
- Passively reabsorbed into the blood
4
Q
Primary site of drug metabolism
A
- Liver
- It is enriched with a variety of enzymes
5
Q
Extra-hepatic metabolism (kidney, lungs, skin) takes place to a smaller extent due to
A
- Presence of
lower level of enzymes
6
Q
Not all drugs are bioavailable, in which this led to the development of
A
- Prodrugs
7
Q
Phase I metabolism (biotransformaiton)
A
- Makes xenobiotics more polar
- Oxidation, reduction, and hydrolysis
8
Q
Phase II metabolism (conjugation)
A
- To further increase polarity by
conjugation - Addition of a new group (acetyl, sulfate, glucuronic acid, amino acid etc.) to the phase I metabolite
9
Q
A drug has no absolute requirement to undergo
A
- Both Phase I and Phase II transformations
- In some instances Phase II transformations are enough to provide adequate water solubility for elimination without the need for Phase
10
Q
Active metabolite may retain
A
- The activity of the parent drug
11
Q
Inactive metabolite has no
A
- Pharmacological activity (unlike the parent drug)
12
Q
Biotransformation
A
- When the metabolite is active, and the parent drug is not
- We call the parent drug a prodrug
13
Q
Phase I metabolism consists of three types of biotransformations
A
- Oxidation
- Reduction
- Hydrolysis
14
Q
Oxidation in phase I occurs via
A
- Mainly Cytochrome P450s (for carbons)
- Flavin-containing monooxygenases (non- carbon) in the liver
15
Q
Miscellaneous oxidases involved in phase I metabolism
A
- Alcohol dehydrogenase, aldehyde dehydrogenase
- Monoamine oxidase (deamination of catecholamines)
16
Q
Reduction in phase I occurs via
A
- Reductase enzymes (e.g. disulfide bond)
17
Q
Hydrolysis in phase I occurs via
A
- Esterases
- Peptidases (hydrolysis of esters and amides)
18
Q
From a chemical perspective, oxidation refers to
A
- Loss of electrons
- Increase in the oxidation state of an atom/molecule
19
Q
The oxidation of a functional group on a drug molecule will result in one or more of the following:
A
- Gain in oxygen
- Loss of hydrogen
- Loss of an alkyl group and/or a loss of a heteroatom
20
Q
Unsubstituted phenyl rings are primarily hydroxylated at
A
- Para position due to a lack of steric hindrance
21
Q
Steric hindrance is also present in _____ and _____ position gets hydroxylated.
A
- Diazepam
- Para
22
Q
Alkene oxidation can produce
A
- Epoxides
- Diols
- Peroxides (as shown with protriptyline)
23
Q
At least one _____ on one of the two alkene carbon atoms is required for this type of oxidation to occur.
A
- Hydrogen atom
24
Q
The _____ present within the structure of tamoxifen cannot undergo oxidation.
A
- Alkene bond
25
A benzylic carbon atom is an _____ carbon atom that is directly attached to an _____.
- Aliphatic
| - Aromatic ring
26
Benzylic oxidation only occurs at the
- Least sterically hindered position
27
An allylic carbon atom is an _____ carbon atom that is directly attached to an _____.
- Aliphatic
- Alkene
- Directly adjacent to a non-aromatic double bond
28
Spironolactone has two allylic carbon atoms; however, only one of these can undergo allylic oxidation because
- The other does not have a hydrogen atom attached to it
29
Aliphatic carbon chains can undergo oxidation at either the _____ in the chain or at the
_____ carbon atom in the chain
- Terminal methyl group (omega/ω)
| - Penultimate/next to last (omega-1/ω-1)
30
Oxidative de-amination mainly occurs with
- Primary amines
31
In order for oxidative deamination to occur
- The α-carbon (i.e., the carbon atom directly adjacent to the nitrogen atom) must be attached to at least one hydrogen atom
- The carbon atom that is α to the amine undergoes oxidation
32
Carbinolamines are _____ and will undergo further reaction to generate either
- Unstable intermediates
| - An aldehyde or ketone (depending upon the nature of the R1 and R2 groups)
33
Oxidative N-dealkylation can occur with
- Secondary or tertiary amines or amides
34
N-Dealkylation of tertiary amines will produce
- Secondary amines
35
N-dealkylation of secondary amines will produce
- Primary amines
36
N-oxidation involves a direct oxidation of the _____ as opposed to an adjacent carbon atom
- Nitrogen atom
37
Primary amines that are attached to a carbon atom that lacks a hydrogen atom can be oxidized to
- Hydroxylamines
| - Nitroso groups
38
ADH enzymes catalyze the oxidation of primary and secondary hydroxyl groups to
- Aldehydes and
| ketones, respectively
39
ALDH enzymes catalyze the oxidation of aldehydes to
- Carboxylic acids
40
Oxidation of functional groups with carbon-oxygen bonds
- ADH: primary/secondary hydroxyl groups to aldehydes and ketones
- ALDH: aldehydes to carboxylic acids
41
Oxidative dehalogenation can remove halogens from _____ and _____ but NOT from ______.
- Aliphatic chains
- Aliphatic rings
- Aromatic rings
42
Summary for oxidation
- Aromatic hydroxylation
- Alkene oxidation
- Oxidation of benzylic carbon
- Oxidation of allylic carbon
- Oxidation of aliphatic and alicyclic carbon
- N-oxidation
- Oxidative dehalogenation
- Oxidative dealkylation
- Oxidative deamination
43
Reduction involves
- Gain of electrons
- Decrease in the oxidation state of an atom or molecule
- Least common phase I metabolic pathway
44
Some of the functional groups that are only present on a very limited number of drug molecules
- Azo group
| - Nitro group
45
Hydrolysis (phase I)
- Addition of a molecule of water across a C—X bond
| - Subsequent cleavage of that bond
46
C—X bond in hydrolysis reactions
- X is an oxygen or nitrogen atom
| - For some functional groups, the carbon atom is replaced by a sulfur or phosphorous atom
47
Hydrolysis readily occurs with
- Esters
- Amides, and their cyclic analogs
- Lactones
- Lactams
48
The hydrolysis of esmolol produces _____, while the hydrolysis of simvastatin converts this prodrug to its _____.
- Inactive metabolites
| - Active metabolite
49
Amides and lactams are hydrolyzed at a slower rate than are
- Esters and lactones
50
Due to rapid ester hydrolysis, procaine has a half-life of
- Less than 1 minute
- Cannot be administered orally
- Used parenterally as a local anesthetic
51
The amide ester of procainamide is hydrolyzed
- Much slower than procaine
52
Phase II metabolism (cojugation)
- Small polar endogenous molecules (such as glucuronic acid, sulfate, or glycine) are
covalently attached to the functional groups of drug molecules to form water-soluble compounds
53
Most conjugation reactions are catalyzed by
- Transferases
54
Glutathione conjugation endogenous compound
- Glutathione (GSH)
55
Acetylation endogenous compound
- Acetyl CoA
56
Methylation endogenous compound
- Methionine
57
Glucoronic acid conjugation endogenous compound
- Glucose-1-phosphate
58
Sulfate conjugation endogenous compound
- Sulfate
59
Amino acid conjugation endogenous compound
- Glycine & glutamine (major)
| - Serine, aspartic acid (minor)
60
Most common phase II reaction
- Glucuronic acid conjugation
61
Glucuronidation substrates
- Phenols
- Alcohols
- Carboxylic acids
- Hydroxylamines
62
Resulting conjugates of glucuronidation are excreted in the urine, or bile if
- MW > 300
63
In phase II glucuronidation, N-or S-glucuronides can be formed from
- Sulfonamides
- Amides
- Amines
- Thiols
64
Compounds than can undergo sulfate conjugation reactions
- Phenols
- Alcohols
- Arylamines
- N-hydroxy
65
Sulfate conjugation reactions are catalyzed by
- Sulfotransferases
66
Drugs with carboxylic acid groups can become conjugated to
- Amino acids (glycine mostly)
67
Carboxylic acid is first activated through formation of a _____, then linked to an amino acid (peptide bond forms)
- Coenzyme A thioester
68
Glutathione is the major antioxidant and called
- The true detoxifying agent
69
Glutathione is present in virtually all mammalian tissues and protects the body from potentially harmful _____.
- Electrophiles (electron pair acceptor)
70
Electrophiles are either initially present within the structure of an _____ or that arise as a product of _____.
- Endogenous or exogenous compound
| - Metabolic processes
71
Acetylation conjugation involves
- Transfer of acetyl groups to a primary amine group, (aliphatic and aromatic amines)
- Amino acids
- Sulfonamides
- Hydrazines and hydrazides
72
The function of acetylation
- Deactivate the drug
73
Methylation conjugation is a minor pathway important in the BIOSYNTHESIS of
- Epinephrine
| - Melatonin
74
Methylation conjugation is a minor pathway important in the CATABOLISM of
- Norepinephrine
- Dopamine
- Serotonin
- Histamine
75
Methylation conjugation is a minor pathway important in MODULATING the activities of
- Macromolecules (proteins and ncleic acids)
76
Methylation conjugation is catalyzed by
- Methyltransferase
77
Methylation conjugation is a minor pathway important in the METHYLATION REACTIONS of
- Amines
- Thiols
- Phenols
78
Phase II summary
- Glucuronidation
- Sulfate conjugation
- Amino acid conjugation
- Glutathione conjugation
- Acetylation conjugation
- Methylation conjugation
