Drug Biotransformation (Exam 1)

Question 1

What is biotransformation

Answer 1

Often termination of activity
Drugs being changed in some way to become active or inactive

Question 2

Where does biotransformation occur most often? Where else can it occur?

Answer 2

Primarily the liver
GI, Lungs, Skin, Kidneys, other tissues, cellular level

Question 3

What happens during the first pass effect

Answer 3

Anything we eat orally has to go through the liver (drug or poison) and significant biotransformation can occur

Question 4

Explain the hepatic portal system for oral drugs

Answer 4

Drug enters intestines it gets absorbed into the intestinal capillairies ->local veins-> hepatic sinuses (leaky capillaries) -> heptaic vein -> vena cava ->systemic circulation

Question 5

Explain the hepatic portal system for drugs given IV

Answer 5

enters systemic circulation ->hepatic artery -> hepatic sinuses -> heptaic vein->vena cava ->systemic circulation

Question 6

Explain the anatomy of hepatic sinusoids

Answer 6

portal vein branch and hepatic artery branch combines to form the blood in the sinuses (very leaky). They contain a mixture of oxy and deoxygenated blood that run though the hepatocytes, site of drug biotransformation -> vena cava -> systemic circulation

Question 7

What two primary ways does the liver biotransform drugs/poisons

Answer 7

Phase 1: add or unmasks a functional group
Phase 2: attaching larger molecules to a substance

xdrugs can go through only one or both

Question 8

How does phase 1 reactions work?

Answer 8

cluster of reactions that convert the drug to a more polar metabolite to be excreted
reactions include oxidation, reduction, dehydrogenation, hydrolysis
mist drugs are inactivated
more readily excreted when hydrophilic

Question 9

What is the primary oxidation pathway for phase 1 reactions

Answer 9

Cytochrome P450

Question 10

How does Cytochrome P450 work

Answer 10

a molecule that converts the drug into a more polar metabolite
1.Drug binds to P450(Fe3+) losses an e- turns into P450(Fe2+)
1.a. Flavoprotein reduces P450(Fe3+) and becomes oxidized and is recycled though NADPH(reducing compound) in the liver
2.O2 is added to P450(Fe2+) and is temporarily attached oxidation reaction losses e-
3.One O attaches to 2 H+ to becom H2O
4. The other O is attaches to the drug and becomes a hydroxyl group -ROH
5. P450(Fe3+) removes from the drug which is more hydrophilic
6. P450(Fe3+) can be used again to attach to a drug

Question 11

What is a characteristic of P450 enzymes and what types are ther

Answer 11

low specificity to bind to different drugs
many diffeten types: CYP3A4/5 metabolize 30% of drugs undergoing phase 1 rxs

Question 12

What are general facts about CYP450

Answer 12

oxidases make drug more hydophilic
over 50 human P450
occurs in the sacroplasmic reticulum
there are variants

Question 13

Name some CYP450 varients and how does that affect drug metabolism

Answer 13

CYP3A4*1 wild type (most common)
it can metabolize slower, faster, or the same rate

Question 14

How does induction of P450 affect drugs

Answer 14

it either enhances synthesis or inhibis degrdation
decreased drug effect if metabolisms deactivates drug
increased drug effect if metabolism activated drug
Drug 1->CYP34A-> Drug 1 (inactive)
Drug 2 an inducer will inactivate drug 1 quickly
- it increases CYP3A4

ProDrug->CYP34A-> Drug 3 (active)
Drug 2 an inducer will activate the ProDrug quickly
-can result in toxicity

Question 15

How does inhibitors of P450 affect drugs

Answer 15

Drug 1->CYP34A-> Drug 1 (inactive)
Drug 4 an inhibitor will keep drug 1 active longer
- it decreases CYP3A4
- can result in toxicity

ProDrug->CYP34A-> Drug 3 (active)
Drug 4 an inhibitor will prevent the ProDrug from being metabolized to the active form

Question 16

What are important CYP450s (3)

Answer 16

2B6 8%
2D6 20%
3A4 50%

Question 17

What are the 7 types of phase 2 conjugation reactions

Answer 17

glucoronidation - attaches a glucose
acetylation- acetly group
glutathiaone
glycine
sulfation
methylation
water

it makes the drug larger and harder to cross barriers and more hydrophilic

Question 18

What is glucuronidation

Answer 18

Uridine diphospate glucuronyltransferase
-adds glucuronic acid from the UDP to the drug
- primarily in the live
- increases aqueous solubility and urinary excretion

Question 19

What is Glutathions-S-transferase (GST)

Answer 19

found everywhere in the cell
high in RBCs
binds and from a glutathione conjugate

Question 21

How can metabolism of drugs produce toxic byproducts

Answer 21

For therapeutic doses utilizes normal detox pathways and no toxic byproducts
In Overdose, normal patways are overwhelmed and alternative pathways are activated leading to toxic byproducts

Question 22

How is tylenol metabolized and how can overdose affect the pathway

Answer 22

Tylenol can go through 2 phase II reactions
1. glucuronidation or sulfation (non-toxic)
2. overdose activates CYP2E1 and CYP3A4 (phase 1 rxs)
3. builds up toxic intermediates that are very reactive
4. it goes through glutathione conjugation (phase II) non-toxic
5. run out of glutathione-> toxic intermediates bind to proteins, cell membranes, carbs and inactivated them ->liver cell death

treatment: N-acetylcysteine recylces glutathione

Question 23

What are extrahepatic metabolism

Answer 23

biotransformation that occurs outside of the liver
plasma: cholinesterase
instestine: less hepatic enzymes
kidney: P450, Glutathiones (GSTs), volatile anesthetics
Brain: P450, psychtropic drugs
Lung: phase I and phase II rxs

Question 24

What other factors affect biotransformation

Answer 24

diet: charcoal inducer CYP1A, grapefruit inhibitor CYP3A
environment: cigarette smoke
Age and Sex: pre v. post pubescent or pedi v adult
disease state: cardiac diseas, liver disease
genetics