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Metabolism Flashcards

1
Q

The lipophilic nature of drugs that allows diffusion across cell mbs & access to their sites of action is also a hindrance, why?

A

It’s a hindrance to their elimination from body (mainly due to reabsorption from kidney tubules back into systemic circulation)

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2
Q

Why is biotransformation of drugs essential?

A

biotransformation (or metabolism) to more water-soluble metabolites is essential to terminate their biological activity & eliminate them from body

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3
Q

What do biotransformation enzymes do?

A

convert lipophilic drugs into highly water-soluble metabolites that are easily excreted from body (mainly in urine & to lesser extent bile/feces)

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4
Q

what is biotransformation?

A

enzyme-catalyzed conversion of 1 xenobiotic into another

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5
Q

for most drugs, their duration of action is inversely proportional to …

A

… the rate at which they are metabolically inactivated

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6
Q

biotransformation of drug is the main determinant of its …

A

… half-life (t 1/2)

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7
Q

How are biotransformation reactions categorized?

A

Either Phase I or Phase II reactions

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8
Q

What is a phase I biotransformation reaction?

A

biotransformation enzymes modify the drug mc mainly by OXIDATION (addition of -OH (hydroxyl) grp to drug)

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9
Q

What is a phase II biotransformation reaction?

A

synthetic reactions that CONJUGATE the drug w/ highly polar endogenous cmpd in cell (ex: carbohydrate, sulphate, or acetate)

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10
Q

How is a drug often biotransformed?

A

Sequentially through both Phase I & II reactions

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11
Q

Where is the most important site for drug biotransformation?

A

Liver

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12
Q

Which tissue has high amts of xenobiotic-metabolizing enzymes?

A

Liver

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13
Q

Which tissues have medium amts of xenobiotic-metabolizing enzymes?

A

lung, kidney, intestine

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14
Q

Which tissues have low amts of xenobiotic-metabolizing enzymes?

A

skin, testes, placenta, adrenals

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15
Q

Which tissue has v. low amts of xenobiotic-metabolizing enzymes?

A

nervous system

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16
Q

What is the important biotransformation reaction in Phase I?

A

Oxidation

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17
Q

What are the important biotransformation reactions in Phase II?

A

Sulphation, glucuronidation, glutathione conjugation, acetylation

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18
Q

What are Cytochrome P450-dependent monooxygenases?

A

(CYPs, aka mixed-fxn oxidases); they are the mjr Phase I oxidative enzymes

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19
Q

where are CYP enzymes located?

A

on smooth endoplasmic reticulum

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20
Q

What do reactions w/ CYP enzymes involve?

A

adding or exposing a polar functional grp (ex: -OH, -COOH, -NH2) to lipophilic drug molecule (catalyze insertion of an oxygen atom into drug mc)
[Rxn: Drug (RH) + O2 + NADPH -> metabolite (ROH) + H2O + NADP+]
(NADPH is electron source)

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21
Q

What other reactions are CYPs involved in other than biotransformation of drugs & other xenobiotics (foreign chemicals)?

A

a wide variety of catabolic & anabolic reactions involving endogenous compounds (ex: steroid hormones)

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22
Q

How many CYP enzymes have been identified and how are they designated?

A

> 100 different CYP enzymes have been identified; designated in families CYP1, CYP2, CYP3 or subfamilies CYP1A, CYP2B, etc. based on DNA sequence similarities

23
Q

Why are CYP enzymes v “versatile” & unique?

A

they have broad & overlapping substrate specificities;
- Broad: 1 enzyme can biotransform many drugs
- Overlapping: 1 drug can be biotransformed by several enzymes

24
Q

CYP enzymes usually inactivate a drug but what else can they do?

A

In certain cases they can BIOACTIVATE a drug to a more pharmacologically or toxicologically active metabolite

25
Biotransformation can result in a metabolite with...
greater pharmacological or toxicological activity
26
once multicellular animals evolved a GI tract, this became a ...
... mjr route of exposure to toxic substances (ex: plant toxins
27
To survive toxic substances, organisms had to...
...evolve a strategy to intercept & detoxify potentially lethal substances. This is first pass drug biotransformation.
28
How does first pass drug biotransformation work?
- accomplished by HEPATIC PORTAL VENOUS SYSTEM, which delivers all substances absorbed from gut to liver (w/ its extensive biotransformation capacity) before they reach systemic circulation & are delivered to rest of body (to exert effects) - this FIRST-PASS EFFECT can result in nearly complete inactivation (>90%) of certain drugs after oral ingestion - for this reason certain drugs are not given orally & are administered via different routes (ex: nitroglycerin given sublingually)
28
What is oral bioavailability?
Fraction of an orally administered drug that reaches the systemic circulation in an unchanged form.
28
The first pass effect lowers a drug's...
... degree of bioavailability
29
What is AUC?
area under the curve
30
Eqn for oral bioavailability?
oral bioavailability = AUC oral / AUC IV
31
What are Phase II biotransformation reactions?
Add (conjugate) a large water soluble grp to an existing functional grp on the mc
32
What do Phase II biotransformation reactions majorly increase?
water solubility (& thus excretability) of drugs
33
What is the major Phase II biotransformation pathway in mammals?
glucaronidation
34
What is the cofactor and enzyme for glucaronidation?
enzyme UDP-glucuronosyl transferase (UDP-GT or UGT) & cofactor UDP-glucaronic acid
35
Where is the enzyme UDP-glucuronosyl transferase located? Where are other Phase II enzymes primarily located?
On the smooth endoplasmic reticulum membrane. Others are primarily in the cytoplasm.
36
Cofactor and enzyme for sulfation?
Sulfotransferase (ST) & cofactor PAPs
37
Cofactor and enzyme for acetylation?
enzyme N-acetyltransferase (NAT) & cofactor acetyl coenzyme A
38
Why cant you give acetaminophen to cats?
B/c Fe dont have or have greatly reduced expression of the glucuronosyl transferase enzyme which is needed to metabolize it
39
what are reactive electrophiles?
reactive oxygen spp & epoxides
40
what is one of our most important defenses against reactive electrophiles?
Glutathione conjugation
41
what is the enzyme and cofactor for glutathione conjugation?
glutathione S-transferase (GST) and cofactor is glutathione (GSH)
42
Glutathione cofactor is in what high concentration in most cells?
mM concentration!
43
how abundant is glutathione S-transferase?
abundant; approximately 5% of cytosolic protein in liver cells
44
Talk about acetaminophen biotransformation:
- Acetaminophen is active ingredient in tylenol - it can go through sulfation or glucuronidation and these are happy pathways - however, it can also be activated by a cytochrome P450 to N-acetyl-p-benzoquinoneimine (or N-acetyl-benzosemiquinoneimine) which wants an electron - it will often get an electron from our bestie glutathione (glutathione conjugation) - if not it can bind to hepatic prots leading to centrilobular necrosis (or to renal proteins w/ damage to kidney medulla) which can cause death by liver failure w/in 24 hours
45
What are the genetic and environmental factors that influence biotransformation?
1. enzyme induction & inhibition 2. intraspecific differences 3. interspecific differences 4. sex & age 5. diet (nutritional factors) 6. disease (underlying pathology)
46
How does enzyme induction & inhibition influence biotransformation?
- CYP enzymes & phase II enzymes can all be induced (increased activity) & inhibited (decreased activity) - v clinically relevant w/ respect to duration of drug action & drug interactions - depletion of cofactors (ex: glutathione) can also be v important
47
How do intraspecific differences influence biotransformation?
- genetic differences (polymorphisms) in expression of enzymes - can result in subset of pop being "poor metabolizers" or even "rapid metabolizers" - classic ex is alcohol dehydrogenase (ADH) in humans
48
How do interspecific differences influence biotransformation?
- recall: hexobarbital sleeping time after same dose - cats are poor glucuronidators (UDP-GT), dogs are poor acetylators (NAT), & pigs are poor sulfators (ST)
49
How do sex & age influence biotransformation?
- sex-specific differences in certain CYP enzymes - in general, v young & old individuals have lower enzyme activities
50
How does diet influence biotransformation?
- certain dietary ingredients can induce or inhibit phase I or phase II enzymes (ex: grapefruit juice inhibits CYP3A4 in humans)
51
How does disease influence biotransformation?
- impaired liver (or kidney) function can decrease biotransformation (or excretion) of drugs

Pharmacology (14 decks)

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