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SAFON - Exam 2 - Dr. Jame's Material

Terms in this set (70)

Which of these factors can affect drug disposition?

A) Route of Administration
B) Interactions of drug with transporter proteins
C) Biotransformation of the drug
D) Drug dose and duration of action
E) A, B, and C only
F) All of the above
F) All of the above
The transport and biotransformation of a drug can influence what factors?
- Distribution of drug
- Uptake of drug
- Elimination of drug

Remember... *DUE*. Distribution, uptake, elimination.
Metabolism (biotransformation) represents the listed clearance mechanism for *what percent* of the top 200 drugs?
73% of the top 200 drugs!

*Renal and biliary excretion accounts for the remainder (moreso renal than biliary). This is often transporter-facilitated*.
Biotransformation can affect *physical-chemical properties* of drugs by doing what?
Increasing their water solubility.

*Biotransformation often results in a more water soluble product!*
Biotransformation can affect the *pharmacological activity* of a drug by doing these three things...
- Turning the active drug into an inactive metabolite.
- Turning the active drug into an active metabolite
- Turning an inactive drug into an active metabolite
Biotransformation can affect the *pharmacological activity* of a drug by doing these three things...

- Turning the active drug into an inactive metabolite.
- Turning the active drug into an active metabolite
- Turning an inactive drug into an active metabolite

*Which of these three processes is the most common?*
- Turning the *active drug into an inactive metabolite.*


(Conversely, turning the active drug into an active metabolite is not very common)
Biotransformation can affect the *pharmacological activity* of a drug by doing these three things...

- Turning the active drug into an inactive metabolite.
- Turning the active drug into an active metabolite
- Turning an inactive drug into an active metabolite

*Which of these three processes would describe a prodrug?*
- Turning an *inactive drug into an active metabolite*
True or false...

Biotransformation affects several drug properties (physical-chemical and pharmacological, to name a couple). Thus, the rate and extent of biotransformation will affect the *duration of action* of the drug.
True!
The conversion of isoniazid to N-acetyl isoniazid would be an example of which scenario?

A) Turning the active drug into an inactive metabolite.
B) Turning the active drug into an active metabolite
C) Turning an inactive drug into an active metabolite
D) None of these guys
A) Turning the active drug into an inactive metabolite.

*This would be a common scenario*

*This specific reaction was a question on the 2013 exam -- #22 - asked about enzyme and what percentage of population were rapid metabolizers - spoiler warning it's 50%*
The conversion of diazepam to N-desmethyl-diazepam would be an example of which scenario?

A) Turning the active drug into an inactive metabolite.
B) Turning the active drug into an active metabolite
C) Turning an inactive drug into an active metabolite
D) None of these guys
B) Turning the active drug into an active metabolite

*This would be an uncommon scenario*
The conversion of Irinotecan (an anticancer drug), to SN-38 would be an example of which scenario?

A) Turning the active drug into an inactive metabolite.
B) Turning the active drug into an active metabolite
C) Turning an inactive drug into an active metabolite
D) None of these guys
C) Turning an inactive drug into an active metabolite

*This is an example of a prodrug!*
What is the most common mechanism in the "activation" of prodrugs?

(what kind of reaction usually occurs to convert them from their inactive form, to their active form?)
Hydrolysis of an ester bond via an esterase.

*Check out slide 7 for a fantastic picture of this happening omg wow reactions yes*
Consider these two statements...

Toxicity related to pharmacological activity will change predictably with metabolism.

Toxicity unrelated to the drug's pharmacological activity is less predictable.

A) Both statements are true
B) Both statements are false
C) 1st statement is true, 2nd statement is false
D) 1st statement is false, 2nd statement is true
A) Both statements are true
*self note: may want to rephrase this question later*

Acetaminophen can form a quinone-imine metabolite. Explain this process and is it an example of toxicity *related to pharmacological activity*, or *unrelated to pharmacological activity*?
This is an example of toxicity *unrelated to pharmacological activity* (because it's an overdose I think, work on this question a bit).

In acetominophen overdose, CYP "shunts" acetominpphen into the quinone-imine metabolite, which can be damaging to the liver and kidney.
What is the main organ of biosynthesis?
The Liver!
Good on you, liver.
What organs can act as sites for biotransformation (that we discussed in lecture)?
Liver, GI tract (particularly small intestine), Lungs, Skin, Kidney, and Brain.
Why is biotransformation important in the kidney?
Helps eliminate some drugs in the urine (makes the more water soluble)
*BLAST FROM THE PAST - BUT THIS TIME SPORTING A FANCY NEW NAME*

Explain pre-systemic biotransformation AKA first-pass metabolism for an orally administered drug.
This means that biotransformation in the intestine and liver will reduce the amount of drug absorbed into the systemic circulation.

Ingested drug gets absorbed across the intestine and taken by the hepatic portal vein the liver. From here it can finally reach main systemic circulation. Biotransformation before this point will reduce levels of the original product in systemic circulation.

*Dosage should be adjusted for drugs with a high hepatic first pass (don't wanna lose too much to first-pass).*
Can drugs administered via other routes experience pre-systemic biotransformation as well?
Yup! Can have pre-systemic biotransformation on the skin (dermal) in in the lung (inhalation). This is usually much less than the oral route. And was said to be "practically negligible" by Dr. James. *So british.*
The Liver and intestine participate in *entero-hepatic cycling* of ______________ following oral or parenteral administration.
Glucuronides. This process affects *MANY* drugs that form glucoronides.
Explain the process of entero-hepatic cycling.
A glucoronide will be absorbed into the liver where it will form a glucoronide conjugate. It will then go into the bile, and be released back into the intestine where it will once again be reabsorbed.

Almost like first pass metabolism in a way - but instead of some of it being biotransformed and like going away or something, some of it is biotransformed and resecreted back into the body in an active form!

Absorbing back and forth forever
))<>((
*Bonus points to the like, 2 people that get this reference*
What factors can influence drug biotransformation?
- Molecular structure of the drug
- Affinity of drug for enzyme
- Amount of drug-metabolizing enzyme
- Availability of co-factors and co-substrates
- Presence of other xenobiotics that affect the amount of activity of the enzyme
What are the "*internal/intrinsic*" individual differences between people that can affect drug biotransformation?
Internal (intrinsic) things that can affect drug biotransformation would be *genetic make-up, age, gender.*

*Can't really change these things*
What are the "*external/environmental*" individual differences between people that can affect drug biotransformation?
External (environmental) things that can affect drug biotransformation would be *nutrition, diet, drugs, supplements, and disease state.*

*These things may change*
How can a person's genetic make-up influence their reaction to a drug?
Single nucleotide polymorphisms (SNPs) in the gene for a drug biotransformation enzyme or transporter protein can *cause individual variability in biotransformation or transport of drugs. *

*Most of these changes are silent mutations, but some aren't!*
A SNP in the coding region of a gene could have what impact?
Could affect the enzyme protein structure (change enzyme affinity for the drug, or the stability of the protein itself)
A SNP in the promotor region of a gene could have what impact?
Could affect regulation of the amount of enzyme expressed (could lead to reduced or increased expression of the affected enzymes protein *via preventing RNA Polymerase from binding*).
CYP2D6 metabolizes many drugs containing __.
N (Nitrogen)
Incidence of altered function or expression of CYP2D6 ("poor metabolizers") varies between what percentages?
Varies between 1-15% of populations. Depends on ethnic group surveyed.
What are the consequences of having altered function or expression of CYP2D6 ("poor metabolizers")?
- May need a lower dose of the drug, to avoid toxicity.
- If the active metabolite is formed via conversion from CYP2D6, poor metabolizers will not response to the drug as well as rapid metabolizers.
Altered function or expression of CYP2D6 was first observed in the 1970s with which drug?
Debrisoquine, an antihypertensive agent.
Why will patient's with altered function or expression of CYP2D6 not get much pain relief from codeine?
Codeine is converted via CYP2D6 to its active form, morphine in the body. Without much CYP2D6 to do the conversion, you won't get much pain relief.
Polymorphisms in CYP2C19 were first shown with the drug _______________.
Mephenytoin
What ethnicities are more prone to poor metabolism via CYP2C19?
High incidence (20-30%) of poor metabolizers among *Japanese and other Asian people.*


(Low incidence (3-5%) of poor metabolizers among Caucasians and Africans)
UGT1A1 belongs to a family of genes that "provide instructions" for making enzymes called UDP-glucuronosyltransferases. What do these enzymes do?
They perform a chemical reaction called *glucuronidation*.

In Glucoronidation, glucuronic acid is attached (conjugated) to a substance.

*UGT1A1 PRODUCES THE ONLY ENZYME THAT GLUCORONIDATES BILIRUBIN, HENCE ITS IMPORTANCE!*

Pulled from: http://ghr.nlm.nih.gov/gene/UGT1A1
Deletion of the UGT1A1 gene will cause which syndrome?

*This syndrome is usually fatal and is associated with severe unconjugated hyperbilirubienmia*

A) Crigler-Najjar syndrome
B) Gilbert's syndrome
A) Crigler-Najjar syndrome

No ability to regulate bilirubin!

*There is no way I will spell this right if I'm actually asked about it on the exam.*
Reduced expression or activity of the *UGT1A1 *(particularly UGT1A1*28*) gene is associated with *Gilbert's syndrome*. This is possibly associated with toxicity associated with which cancer drug?
Irinotecan treatment (for colon cancer)

(But recent evidence suggests other UGT1A family polymorphisms contribute to toxicity associated with irinotecan as well. So UGT1A1 is not entirely to blame.)

*GILBERT'S SYNDROME HAS BEEN ASKED IN SOME CAPACITY ON BOTH THE 2012 AND 2013 EXAM. PROBABLY WOULD BE A GOOD IDEA TO GET COZY WITH IT*
Why are people with Gilbert's syndrome more likely to experience toxicity associated with Irinotecan treatment?
Irinotecan is biotransformed in the body into the active ingredient (SN-38) via hydrolysis. The body then converts some of the the active ingredient into an inactive ingredient via *UGT1A1 and other UGT1A isoforms*.

*Without the ability to convert away enough of the active ingredient, people with Gilbert's syndrome will likely accumulate too much of the active ingredient.

Thus they are more to have toxicity problems associated with Irinotecan. They may need to be given a lower dose, or a different drug entirely.*
True or false...

Newborns have high levels of UGTs, thus drugs that are cleared via glucuronidation can be used no problem.
False!

Newborns have *low levels of UGTs*, thus drugs that are cleared via glucuronidation *must be used with CAUTION!*

*Was referred to on the 2012 exam.*
Some newborns develop "physiological jaundice" because of their inability to clear bilirubin. How is this treated?
This is treated by putting the baby under UV light. Zaps all the excess bilirubin outta them.
True or false...

There is a general decline in metabolizing ability in old age.
True

*See chart on page 32. Yes, drug metabolizing enzymes do decrease as you age, but not by a tremendous amount.*
Explain how N-acetyltransferase (NAT-2) polymorphisms are relevant in the utilization of isoniazid to treat tuberculosis.

(Like, why would you want to be careful in using isoniazid to treat someone with a NAT-2 polymorphism that causes them to be a slow metabolizer?)
Isoniazid is the active ingredient. Normally the body would acetylate isoniazid to its inactive form (N-acetylisoniazid).

People with NAT-2 polymorphisms will often become slow metabolizers of isoniazid. This will cause them to have higher blood levels of isoniazid, and thus make them more susceptible to toxicity issues.
The incidence of NAT-2 polymorphisms causing slow acetylation in the US is about ____ percent.
50%

People with such polymorphisms would convert isoniazid to its inactive metabolite slower than those without such polymorphisms.
When dealing with NAT-2 polymorphisms, how could you deal with slow acetylators? What about rapid acetylators?
Slow acetylators: May have to reduce dosage (since toxicity is a concern)

Rapid acetylators: May have to increase dosage (since drug may otherwise be ineffective)
Some people have extra copies of the CYP2D6 gene. What are the results of this?
Increased CYP2D6 expression, leading to "ultra-rapid" metabolism of CYP2D6 drug substrates.

*Worth noting that the percentage of ultra-rapid metabolizers (URMs) is very low. Theres not a ton of poor metabolizers already, and URMs make up only a fraction of that*.
True or false...

Some drugs and foods are able to upregulate or induce particular forms of CYP450 and other drug-metabolizing enzymes. The extent of induction varies with the dose or exposure level, and the potency of the inducer.
True
Omeprazole induces which CYP enzyme(s)?

A) CYP1A
B) CYP2
C) CYP3
D) CYP2E1
E) CYP3A4
F) CYP3A5
G) CYP4
H) B and C
I) E and F
A) CYP1A
Phenobarbital and carbamazepine induce which CYP enzyme(s)?

A) CYP1A
B) CYP2
C) CYP3
D) CYP2E1
E) CYP3A4
F) CYP3A5
G) CYP4
H) B and C
I) E and F
H) B and C

so... CYP2 and CYP3

Side note: Phenobarbital and other barbituates can also induce UGT and GST.
Rifampin induces which CYP enzyme(s)?

A) CYP1A
B) CYP2
C) CYP3
D) CYP2E1
E) CYP3A4
F) CYP3A5
G) CYP4
H) B and C
I) E and F
I) E and F

so... CYP3A4 and CYP3A5
Isoniazid induces which CYP enzyme(s)?

A) CYP1A
B) CYP2
C) CYP3
D) CYP2E1
E) CYP3A4
F) CYP3A5
G) CYP4
H) B and C
I) E and F
D) CYP2E1
Clofibrate induces which CYP enzyme(s)?

A) CYP1A
B) CYP2
C) CYP3
D) CYP2E1
E) CYP3A4
F) CYP3A5
G) CYP4
H) B and C
I) E and F
G) CYP4
Describe the steps in the induction of drug-metabolizing enzymes.
hint: first step is...

- At rest, the receptor will be bound to another proteins in the cytoplasm.
- At rest, the receptor will be bound to another proteins in the cytoplasm.
- The drug will bind to the receptor in the cytoplasm, and displace the other protein.
- The drug-receptor complex translocates to the nucleus of the cell
- The drug-receptor complex dimerizes with a second nuclear protein
- The drug-dimer complex binds to the drug receptor recogition site on the promoter region in DNA.
- This binding initiates synthesis of the mRNA for the induced enzyme
- mRNA is translated to protein.

*May want to know how to draw the diagram of this! Was on a previous exam and this is something I know I would miss otherwise.*
Tobacco smoke, and charcoal-broiled food can induce which enzyme(s)?

A) CYP1A2
B) CYP1
C) CYP2
D) CYP2E1
E) CYP3A4
F) both B and C
A) CYP1A2
Ethanol induces which enzyme(s)?

A) CYP1A2
B) CYP1
C) CYP2
D) CYP2E1
E) CYP3A4
F) both B and C
D) CYP2E1

CYP2*E*1 - *E* = ethanol

Or, in the immortal words of Daniel Hawkins - *2* people + alcohol (aka *e*thanol) = *1* baby. *2E1*
St. John's worth induces which enzyme(s)?

A) CYP1A2
B) CYP1
C) CYP2
D) CYP2E1
E) CYP3A4
F) both B and C
E) CYP3A4

*Example of why you'd wanna see what herbal supplements a patient is taking as well! Many drugs are metabolized via CYP3A4 and may render them less effective or ineffective.*
What are the consequences of enzyme induction?

(3 things mentioned in lecture)
- Induced enzymes will lead to greater biotransformation of their respective drugs.
- The inducing agent may be a substrate for the induced enzyme.
- Doses of drugs metabolized via P450 may need to be adjusted.

(so, increased biotransformation of substrates and potentially the inducer itself. Also dosages may need to be altered)
Explain why taking Rifampin/steroids along with oral contraceptives might not be the greatest idea.

(hint hint: has to do with CYP-somethingsomething)
Rifampin will induce CYP3A4. The ethynylestradiol in oral contraceptives will be metabolized by said CYP3A4. This leads to reduced effectiveness of the oral contraceptive and may lead to a surprise baby.

TL;DR: Rifampin/steroids induces CYP3A4. Makes birth control less effective.
Explain how constantly consuming charcoal-broiled food and tobacco smoke could have an effect on a patient taking theophylline.

(Theophylline is a medication used to control asthma)
Charcoal-broiled foods will induce CYP1A2. Theophylline will be metabolized by said CYP1A2, thus rendering the Theophylline dose ineffective.

*Same case as the rifampin/steroid and birth control. But this is just through a different enzyme*.
Bioflavonoids, garlic, onions, green and black tea, and preservatives such as BHA, and BHT are examples of which kinds of inducers?
*Weak* inducers. This means they have low potency, or that the amount consumed usually isn't enough for induction.
Cytokines produced during infectious diseases can have what effect on drug-metabolizing enzymes?
Can down-regulate drug-metabolizing enzymes

(for example, interferon down-regulates CYP2 and CYP3 family members)

*Liver disease, such as cirrhosis, can also lead to lowered drug-metabolizing enzymes.*
Which form of CYP is the most prevalent (makes up the most percentage of total CYP) in the liver?
CYP*3A4/5*. Makes up ~28% of total CYP content of liver.
Which form of CYP in the human liver has the most variability?
CYP*2D6*. Can vary in over 1000 different ways. So exciting!
Which form of CYP is responsible for a greater amount of drug metabolism, CYP3A4, or CYP2D6?
CYP3A4. Makes up almost half of the chart on slide 54.

(CYP2D6 comes in second, making up almost a quarter of the chart)
True or false

Ethanol consumption leads to lower GSH concentrations.
False!

Ethanol consumption leads to lower NADPH concentrations, and may reduce drug monooxygenation.

Poor nutrition leads to lower GSH concentrations. And similarly, protein-calorie malnutrition leads to lowered free AAs and reduced AA conjugation.
Drug-drug interactions can lead to inhibition of monooxygenation.

Explain why this can be beneficial in the treatment of AIDS via Ritonacir, indavir and saquinavir.
They are all CYP3A4 substrates. Thus these 3 drugs all compete for the same pathway. This drug interaction is *intentionally* exploited by giving ritonavir along with indinavir or saquinavir. This allows for you to essentially "brute force" our way through metabolism. CYP3A4 can only metabolize so much, so you will have more ritonavir being absorbed in the intestine (so it can actually be used) instead of being metabolized.

TL;DR: You're taking a battering ram made out of substrates to the CYP3A4 castle gates.
What's special about imadazole-containing drugs?

*self note: review this portion of the lecture tonight*
They have a lone pair of electrons on the Nitrogen, which occupy the oxygen-binding site of CYP450. This can prevent oxygenation of other drugs that are CYP substrates.
Grapefruit juice is shown to impact drug bioavailability. How?
A component of grapefruit juice inhibits CYP3A*(4? - is it missing because of a typo? FIND OUT!)* and an important efflux transporter, the p-glycoprotein (MDR1). This can cause problems for drugs that are substrates for CYP3A4 and p-glycoprotein - which deal with many common drugs.

*Slides 66 and 67 contain some nice pictures on this*
Drug-metabolizing enzymes increase what two factors?
- Water solubility of a drug
- Elimination
Do newborn infants have lower levels of UGT1A1?
You bet they do
Give two reasons why an individual patient may show slow metabolism of a drug that is mainly cleared by UGT1A1.
- Patient is a newborn
- Patient has Gilbert's syndrome.

*Why is Crigler-Najjar syndrome not listed? These two conditions above lead to reduced levels of UGT1A1, while Crigler-Najjar syndrome deletes the gene entirely. So Crigler-Najjar syndrome will not process this drug at all in comparison to the two conditions listed. I'm just making this assumption though. It was never explicitly stated anywhere from what I remember.*
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