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Flashcards in Pharmacokinetics Deck (44):

What is a xenobiotic?

Any foreign chemical from the body


What is the main property that drug metabolism seeks to promote?

Hydrophilicity -> in order to be excreted

A lipophilic drug would persist in the body for long periods of time if unchanged. Some drugs which are ionized at physiological pH can be excreted from the body even without metabolism


What is the mechanism of Tylenol toxicity?

Low levels - drug is metabolized by sulfation or gluconuration

High levels - CYP2E1 metabolizes it to a toxic intermediate called NAPQI. Some can be detoxified by glutathione conjugation, but the rest causes hepatotoxicity by reacting with cellular macromolecules


What are some pathophysiological conditions which can alter drug metabolism?

1. Liver disease - altered hepatic metabolism
2. Cardiac disease - reduced blood flow to liver (reduction of metabolism of flow-limited drugs)
3. Metabolic abnormalities such as diabetes, inflammation, or infection can alter enzymatic expression


What are the four basic categories of biotransofmration reactions? What "phase" do each of these fit in?

1. Oxidation - Phase 1
2. Reduction - Phase 1
3. Hydrolysis - Phase 1
4. Conjugation - Phase 2


What is Phase 3 metabolism?

Term sometimes used to describe the transporter proteins that "pump" xenobiotics or their conjugates out of cells


Does phase apply a specific order to metabolism?

No, in fact in some rare cases such as the metabolism of the TB drug isoniazid, phase 1 metabolism is preceded by phase 2 metabolism


What is biotransformation, and is it always catalyzed by enzymes?

Biotransformation = another name for drug metabolism

Not always catalyzed via enzymes:
1. Reactions occurring at an appreciable rate without enzymes
2. Reactions catalyzed by gastric acid


What are the general characteristics of enzymes carrying out biotransformation?

Limited number of enzymes with broad substrate specificities -> CYP2D6 and CYP3A4 metabolize over half of orally effective drugs in use


What is a "first pass effect"?

Metabolism of xenobiotics by intestines / liver can markedly limit the bioavailability of orally administered drugs


Where are xenobiotic-metabolizing drugs present?

Widely throughout the body, including kidney, lung, skin, and nasal epithelium


What are some atypical enzymes which contribute to biotransformation of drugs?

1. Gut microflora enzymes
2. Intermediary metabolism enzymes - i.e. Beta-oxidation enzymes in some processes


What is meant in saying xenobiotic-metabolizing enzymes are inducible?

There are sensory receptors which can tell how much xenobiotic drugs there are, causing upregulation of metabolic enzymes


Does metabolization via xenobiotic-modifying enzymes always change the pharmacological activity?

No -> the effect can be negative, positive, or unchanging. For instance, O-demethylation of codeine yields morphine.


How does biotransformation change the toxicity of the substrate?

Can make it more (bioactivation) or less toxic (detoxification)


What is the most important type of enzyme for xeno-biotic modification and what does it do?

cytochrome P450s, due to catalytic versatility and number of xenobiotics it detoxifies / bioactivates

It oxidizes substrates -> a gain of oxygen or loss of hydrogen atoms which signifies a loss of electrons


What is a microsome and why is it relevant?

They are vesicles of purified liver endoplasmic reticulum in vitro, which contain large numbers of detoxification enzymes


What are some of the endogenous metabolic functions of CYPs?

Steroidogenesis (in mitochondria)
Cholesterole and bile acid synthesis / metabolism
Fatty acid / eicosanoid metabolism
Vitamin D and A metabolism


What is an orphan P450?

CYPs which have no currently known function


What functional group do CYP's contain?

A heme group which plays an important role in oxidation catalysis


What is meant by CYP3A4? What do family and subfamily mean?

Cytochrome P450, family 3, subfamily A, gene 3

Family: Group of CYPs with at least 40% amino acid sequence homology
Subfamily: Group of CYPs within a family with at least 55% sequence homology


How does each CYP know when to be expressed?

Although many will have overlapping specificity, they are generally expressed during development with some tissue specificity (not just liver).

Furthermore, they are inducible by certain drugs


What is the basic reaction catalyzed by CYP? How does it work? What provides the energy for the reaction?

Monooxygenation, where an O2 is used. One oxygen is incorporated into the substrate to oxidize it(RH->ROH), the other is reduced to water. The reducing power comes via NADPH.


What relays in electrons to CYP in microsomal CYPs?

the NADPH-cytochrome P450 oxidoreductase (utilizes a flavin group to do single electron transfers) - also known as P450 reductase


What is the mechanism of action of CYP450s?

1. RH drug binds to CYP with its heme iron in Fe+3 state.
2. First electron is provided by P450 reductase, reducing the iron to +2.
3. Molecular oxygen binds, and second electron is donated to oxygen by P450 reductase or cytochrome b5 (giving it a -1 charge).
4. One oxygen gains the second electron from Fe+2 as well as two protons, forming water (the reduction). The other oxygen is incorporated into the substrate as ROH (oxygen is reduced here as well, but the substrate is oxidized).


Why are not all products created by CYPs alcohols or phenols?

Due to rearrangement reactions

-> i.e. epoxidation, heteroatom oxygenation or N-oxygenation (adding an oxygen to a sulfur or nitrogen), O-dealkylation (as when codeine is hydroxylized and formaldehyde is lost, forming morphine).


What is a flavin mono-oxygenase and how is it different than a CYP?

One of the many other oxidative enzymes which can be used in Phase 1 oxidation other than CYPs

Carries out N, S, or P oxidization, unique in that they do not require another protein such as P450 reductase to transfer the electrons


What generally catalyzes azo and nitro reduction?

Intestinal microflora, but sometimes CYPs


What generally catalyzes carbonyl and quinone reduction? What is the required substrate?

Aldo-keto reductases
Short chain dehydrogenases / reductases
Quinone oxidoreductases

Required substrate: NADPH to provide electrons to carry out the reduction.


List two major groups of enzymes that carry out hydrolysis reactions?

1. Carboxylesterases -> as in the hydrolysis of novocaine
2. Epoxide hydrolases -> including microsomal and soluble


How do epoxide hydrolases function and why are they important?

Trans-addition of water to epoxides to form alcohols

Important for detoxifying electrophilic epoxides which can bind proteins and nucleic acids and cause toxicity. They will break up epoxides formed by CYP450s so they are expressed in the same cells to detoxify them


In what rare scenario can epoxide hydrolases cause toxicity?

Generally, they are detoxification enzymes for CYP450 products. However, sometimes the alcohol products they form can still be metabolized by CYPs, leading to an epoxide which cannot be processed and ultimately a toxic product down the road (i.e. chemotherapy drug with adverse effects)


What is the general goal of phase 2 metabolism? Does this always work?

Conjugating metabolites to be more polar than the substrate, making them pharmacologically inactive and more readily excreted.

This is not always true: they can become more toxic, less polar (methylated or acetylated), and are still active (i.e. morphine 6-glucuronide)


What are six major conjugation reactions?

1. Glucuronidation
2. Sulfation (sulfonation)
3. Glutathione conjugation
4. Acetylation
5. Methylation
6. Amino acid conjugation


What is a UGT and where do they localize to?

UDP-glucuronosyltransferases (UGT)

Transfer glucuronic acid from UDP-glucuronic acid to a nucleophilic heteroatom on a substrate

They localize to microsomes


What is a heteroatom?

An atom other than carbon or hydrogen


What co-factor is required for sulfonation reaction, and what is one substrate which cannot be used?

PAPS - 3-phosphoadenosine-5'phosphosulfate

Sulfate cannot be attached to a carboxylic acid, usually alcohols, phenols, and nitrogens


What enzymes catalyze sulfonation?

Cytosolic sulfotransferases (SULTs)


What is glutathionation and what enzyme catalyzes it?

Transfer of glutathione to an electrophilic atom (i.e. epoxides)

Glutathione = Glutamate-Cysteine-Glycine, attachment via SH of cysteine

Catalyzed by glutathione transferases (localized to cytosol, microsome, or mitochondria)


What is acetylation and what cofactor is required? What is the substrate?

Transfer of an acetyl group via acetyl-coenzyme A to an amino group on a substrate


What enzyme catalyzed acetylation?



What is the cofactor for methylation and what enzyme carries it out?

S-adenosylmethionine, carried out by methyltransferases


What is the general substrate for methyltransferases?

Electron-rich heteroatoms, although some metals can be used.

Generally makes products which are less hydrophilic, except in some niche cases (i.e. makes a quaternary amine which is charged)


What are the two types of reactions which occur for amino acid conjugation?

1. Conjugation of carboxylic acid to glyine, glutamate, or taurine via intermediate activation with CoA

2. Conjugation of aromatic hydroxylamine via aminoacyl tRNA synthetase. Literally add via carboxylic acid and it looks like a peptide bond of a protein.