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z Biopharm > Metabolism > Flashcards

Metabolism Flashcards

1
Q

(T/F) There is a potential for metabolism at every step of pharmacodynamics.

A

True!

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2
Q

(T/F) Biliary excretion is composed only of parent molecules while urine is composed of both parent molecules and metabolites.

A

False, excretion = parent molecules + metabolites, urination = parent molecules only.

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3
Q

What is the primary objective of xenobiotic metabolism?

A

To deactivate and facilitate the elimination of xenobiotics from the body.

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4
Q

What is the primary obstacle of xenobiotic metabolism?

A

Lipophilic nature of xenobiotics. Lipophilicity hinders elimination; kidney can reabsorb them back into circulation while hydrophilic excreted in urine.

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5
Q

What are the primary sites of xenobiotic metabolism?

A
  1. LIVER
  2. small intestine
  3. kidney, lungs, skin, brain…
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6
Q

Primary products are what parent molecules are metabolized to. What are the four possibilities of primary products?

A
  1. More polar/charged metabolites
  2. Inactive metabolites of active substance (most drugs)
  3. Active metabolites of active substances
  4. Active metabolites of inactive substances
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7
Q

Metabolization obeys Michaelis-Menten kinetics. What is the difference between the first and zero order kinetics?

A

1st order - a constant FRACTION of substrate is metabolized per time; assuming mechanisms are NOT SATURATED.

0 order - a constant AMOUNT of substrate is metabolized per time, followed when mechanisms are SATURATED.

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8
Q

Match the phases of metabolism to their definition:

  1. Phase 0
  2. Phase I
  3. Phase II
  4. Phase III

A. metabolic modification (to make it less lipophilic); produces primary products
B. transport of metabolized xenobiotics out of cell through EFFLUX pumps. no enzyme involvement
C. transport of drugs into the cell through UPTAKE pumps. no enzyme involvement
D. conjugation; produces secondary products

A

Phase 0 - transport of drugs into the cell through UPTAKE pumps. no enzyme involvement

Phase I - metabolic modification (to make it less lipophilic); produces primary products

Phase II - conjugation; produces secondary products

Phase III - transport of metabolized xenobiotics out of cell through EFFLUX pumps. no enzyme involvement

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9
Q

(T/F) All xenobiotics go through phase I, phase II and then are excreted out.

A

False, some can directly be excreted, some can skip phase I.

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10
Q

While Phase I metabolites are generally _____ polar and active (+ toxic) than parent, Phase II metabolites are generally _____ active than parent and Phase I metabolites.

A

more; less

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11
Q

Match the following terms to their definition:

  1. Inducers
  2. Inhibitors

A. Inhibit the activity of enzymes. Decrease biotransformation, increase plasma concentration of parent, increase effects if metabolite is inactive, decrease effects if metabolite is active.

B. Elicit increased activity of enzymes. Increase biosynthesis, increase biotransformation, decrease plasma concentration of parent, decrease effects if metabolite is inactive or increased effects if metabolite is active.

A

Inducers; elicit increased activity of enzymes. Increase biosynthesis, increase biotransformation, decrease plasma concentration of parent, decrease effects if metabolite is inactive or increased effects if metabolite is active.

Inhibitors; inhibit the activity of enzymes. Decrease biotransformation, increase plasma concentration of parent, increase effects if metabolite is inactive, decrease effects if metabolite is active.

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12
Q

Which out of the two (inhibitors/inducers) reduce drugs effects but increases pro-drugs effects?

A

Inducers!

More of active drugs are being metabolized; less active!

More of pro-drugs being metabolized; more active!

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13
Q

Match the following terms to their definition:

  1. Competitive inhibitors
  2. Non-competitive inhibitors
  3. Uncompetitive inhibitors

A. structurally different from substrates and binds at allosteric sites when substrate is bound to enzyme (ES complex)
B. structurally similar to substrates and compete to bind at active site of enzyme.
C. structurally different from substrates and bind at allosteric sites to reduce enzyme activity.

A

Competitive inhibitors - structurally similar to substrates and compete to bind at active site of enzyme.

Non-competitive inhibitors - structurally different from substrates and bind at allosteric sites to reduce enzyme activity.

Un-competitive inhibitors - structurally different from substrates and binds at allosteric sites when substrate is bound to enzyme (ES complex)

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14
Q

Out of the three main types of inhibition, in which can increasing the substrate concentration overcome the inhibition?

A

Competitive inhibition.

In other cases of inhibition, the efficacy of enzyme is affected unlike in competitive inhibition.

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15
Q

Match the following terms to their definition:
1. Competitive inhibitors
2. Non-competitive inhibitors
3. Uncompetitive inhibitors

A. both Vmax and Km decrease
B. Vmax decreases and Km remains same
C. Km increases and Vmax remains the same

A

Competitive inhibitors - Km increases and Vmax remains the same
Non-competitive inhibitors - Vmax decreases and Km remains same
Uncompetitive inhibitors - both Vmax and Km decrease

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16
Q

What is suicide inhibition?

A

IRREVERSIBLE INACTIVATION; enzyme binds to a substrate analog and forms an irreversible complex with it through a covalent bond.

Grapefruit has suicide inhibitors; can increase bioavailability of drugs.

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17
Q

Phase I enzymes are located predominantly in ______ cells, which are also known as ________.

A

Liver; hepatocyte

18
Q

Which endoplasmic reticulum is responsible for xenobiotic metabolism? What is the other one responsible for?

A

Smooth endoplasmic reticulum is responsible for xenobiotic metabolism.

The rough endoplasmic reticulum is responsible for protein synthesis (has ribosomes).

19
Q

What are two common reactions of phase I enzymes?

A
  1. Add reactive groups
  2. Remove/replace groups to increase polarity
20
Q

What proteins is the cytochrome P450 superfamily composed of?

A

Heme-thiolate proteins

21
Q

What is the most simplified reaction of CP450?

A

Oxidation

22
Q

Are CYPs highly expressed in extrahepatic tissue?

A

No!

23
Q

Basal expression and up-regulation of CYPs in extra-hepatic tissues can affect local _______ and _______.

A

disposition; toxicity

24
Q

We often use animals, like rodents, to study the metabolization of drugs in humans. Why does the data collected in rodents not 100% reflect how a xenobiotic is metabolized in humans?

A

Humans have half of the number of CYP functional genes that rodents have.

Rodents have 102 putatively functional genes of Cytochromosome P450 superfamily, while humans have 57.

25
Q

In P-450 CYP2D*6, what does the 2 represent? What does the D represent? What does the 6 represent?
What does the * separate?

A

2 = family
D = subfamily
6 = Isoenzyme

The * separates the gene and the allele. (gene*allele)

26
Q

What is polymorphic distribution?

A

Different alleles of same enzymes (CYPs) result in different enzymatic capacity in one species. If the alleles are less functional, they result in an enzyme that is a poor metabolizer.

It is responsible for individual variability. A group of population may not be as affected by drugs because the metabolize it ultra rapidly, while another group may highly be affected because they poorly metabolize it.

27
Q

How would the following factors impact Ke and the expected bioavailability?

  1. Inhibitions of metabolic enzymes
  2. Induction of metabolic enzymes
  3. Poor metabolizer phenotype
  4. Ultra-rapid metabolizer phenotype
A
  1. Inhibitions of metabolic enzymes; lower elimination, smaller Ke, greater bioavailability
  2. Induction of metabolic enzymes; higher elimination, higher Ke, lower bioavailability
  3. Poor metabolizer phenotype; lower elimination, smaller Ke, greater bioavailability
  4. Ultra-rapid metabolizer phenotype; higher elimination, higher Ke, lower bioavailability
28
Q

Why kind of CYP family do smokers and firefighters express more of and why does this lead them to have a higher risk of cancer?

A

Smokers and firefighters express more CYP1 family.

CYP1 Family are induced by POLYCYCLIC AROMATIC HYDROCARBONS (PAH) which is found in cigarette and smoke. PAH activate compounds to carcinogens.

29
Q

(T/F) There are several endogenous substrates of the CYP1 family, while there are no endogenous substrates of the CYP2 family.

A

False, there are no endogenous substrates of the CYP1 family while there are some of the CYP2 family.

30
Q

What is the largest CYP family in humans?

A

CYP2

31
Q

For many drugs, like nicotine, there are many pathways of metabolization. What pushes metabolization of these drugs from one pathway to another? Name 3.

A
  1. Polymorphism
  2. Presence of inducers
  3. Presence of inhibitors

*these change the pharmacokinetics of the drug

32
Q

What is the difference between the R-Warfarin and S-Warfarin?

A

Stereoselective CYP-mediated oxidation

R-Warfarin highly metabolized through various metabolic pathways.

S-Warfarin less metabolized, has significantly less pathways. It is the more active isomer because it is eliminated slower.

33
Q

(T/F) All substances metabolized through CYP enzymes are at a risk of being competitive inhibitors of any other substrate for the same enzyme.

A

True!

34
Q

Describe the drug drug interaction of fluoxetine (Prozac) and tamoxifen (Nolvadex).

A

Fluoxetine inhibits CYP2D6 (the enzyme that metabolizes it). The breast cancer pro-drug, tamoxifen, requires the enzyme to metabolize it so it can turn into an active drug. When there is more of the inhibited form of the enzyme, there is more of the pro-drug, and less of the active drug.

The cancer drug, then, becomes less effective.

In simpler terms, fluoxetine blocks activation of tamoxifen. COMPETITION INHIBITION.

35
Q

Match the following CYP families to their definitions:

1) CYP1 family
2) CYP2 family
3) CYP3 family

a) most abundant of P450 liver form. BROAD substrate specificity; lots of drug-drug interactions
b) no known endogenous substrates, inducible by PAH that can activate compounds to carcinogens
c) largest family in humans; endogenous + exogenous substrates

A

CYP1 family - no known endogenous substrates, inducible by PAH that can activate compounds to carcinogens

CYP2 family - largest family in humans; endogenous + exogenous substrates

CYP3 family - most abundant of P450 liver form. BROAD substrate specificity; lots of drug-drug interactions.

36
Q

What are the other Phase I enzymes besides CYPs?

A
  1. Epoxide hydratases (hydralases)
  2. Alcohol dehydrogenases (ADH)
  3. Aldehyde dehydrogenases 1 (ALDH)
  4. Carboxylesterases (acetylcholinesterase)
  5. Flavin-dependent mono-oxygenase (FMO)
  6. Monoamine oxidase (MAO-A/B)
37
Q

(T/F) Phase I enzymes oxidize and add reactive groups. They make molecules more polar so they are less likely to go through membranes and re-enter circulation.

A

True!

38
Q

Which phase enzymes need cofactors?

A

Phase II

39
Q

What are the five phase II enzymes and what are their mechanisms?

A
  1. Methyltransferases - methylation
  2. N-acetyltransferases - acetylation
  3. Sulfotransferases - sulphation
  4. UDP-glucuronosyl transferases - glucuronidation
  5. Glutathione S-transferases - glutathione conjugation
40
Q

Which phase II enzymes add big, bulky polar molecules?

A

Sulfotransferases, UDPGT, and glutathione s-transferases

41
Q

Which phase II enzymes make their products more lipophilic?

A

Methyltransferases and N-acetyltransferases

z Biopharm (9 decks)

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