Drug Metabolism and BBB

Question 1

Drug metabolism

Answer 1

aka “biotransformation”
the process by which enzymes in the body catalyze reactions that change the chemical structure of a drug

Question 2

principal site of drug metabolism

Answer 2

liver and GI tract

Question 3

Goal of drug metabolism

Answer 3

to make drugs easier to excrete

Question 4

Phase 1 enzymes/ reactions of metabolism

Answer 4

add or create a reactive group on the drug, to create a site for a phase II enzyme to add a large polar group (e.g. oxidation, reduction, hydrolysis)

Question 5

Phase II reactions of metabolism

Answer 5

add a large polar group via conjugation reactions to make the drug water-soluble, easier to excrete

Question 6

Metabolic inactivation

Answer 6

most commonly, metabolism converts a pharmacologically active drug (most are lipid-soluble) to a hydrophilic form that is more readily excreted in urine, but is no longer pharmacologically active

Question 7

Metabolic bioactivation

Answer 7

some drugs are administered as a prodrug which becomes active (or more active) when metabolized. Example: cyclophosphamide

Question 8

Metabolic toxicity

Answer 8

products of drug metabolism can sometimes be toxic. Example: Tylenol

Question 9

Cytochrome P450 enzymes

Answer 9

aka P450s or CYPs are a very large family of enzymes that catalyze Phase I reactions; most are metabolized by CYP enzymes, especially CYP 3A4, 2D6 and 2C9

Question 10

UGTs (UDP-glucuronosyltransferase enzymes)

Answer 10

one family of enzymes that catalyzes the largest fraction of Phase II reactions

Question 11

conjugation reactions

Answer 11

includes methylation, sulfonation, acetylation, glucuonidation; occurs during Phase II metabolism

Question 12

Enzyme induction

Answer 12

a process whereby a drug increases the expression of an enzyme (causes the body to make more copies of the enzyme by increasing gene transcription and expression); results in an increased metabolite production and decreased concentrations of parent or precursor drug

Question 13

Enzyme inhibition

Answer 13

a process whereby a drug or other chemical decreases the rate of metabolism of a substrate (most commonly, by competing for the active site on the enzyme); results in decreased production of metabolites and increased concentration of parent or precursor drug

Question 14

How is the exchange of chemicals between blood and CNS regulated?

Answer 14

tightly regulated by specialized endothelial or epithelial cells (termed blood-tissue barriers)

Question 15

sites with protective blood-tissue barriers

Answer 15

brain, placenta, retina, testis, thymus

Question 16

paracellular diffusion

Answer 16

extremely rare (due to tight seals between brain endothelial cells called tight junctions) so uptake of water-soluble molecules into brain is very limited by this route

Question 17

transcellular lipid diffusion

Answer 17

allows many small lipophilic and gaseous molecules to cross brain endothelial cells into brain (most substances that enter brain enter by this route)

Question 18

lipid diffusion

Answer 18

operates along a concentration gradient; requires no energy

Question 19

measure of lipophilicity

Answer 19

LogP (the partition coefficient), measured by comparing partitioning of a compound into a lipid (octanol) vs. water layer (LogP); high logP value = highly lipophilic; low logP value = hydrophilic

Question 20

transport proteins

Answer 20

allow uptake of specific key nutrients and substrates such as amino acids and glucose

Question 21

transcytosis (receptor-mediated and absorptive)

Answer 21

involve bulk packaging of many types of substrates into vesicles for delivery across the BBB

Question 22

How do substances move in and out of the blood outside of the CNS?

Answer 22

via capillaries

Question 23

special CNS capillary structural features that strictly limit entry of fluids/water-soluble compounds into the brain

Answer 23

1. tight junctions
2. no fenestra (pores)
3. few pinocytotic vesicles
4. a net negative charge on BEC
5. microglia near vessels
6. thick basement membrane
7. pericytes
8. astrocytes

Question 24

tight junctions

Answer 24

specialized structures form a nearly impenetrable seal between endothelial cells, preventing movement of ions or molecules between endothelial cells

Question 25

no fenestra (pores)

Answer 25

limits entry of small molecules and proteins

Question 26

few pinocytotic vesicles

Answer 26

minimizes entry of extracellular fluid, which contains sugars and proteins

Question 27

a net negative charge on BEC

Answer 27

limits entry of anions into brain

Question 28

microglia near vessels

Answer 28

restrict pathogen entry into brain

Question 29

pericytes

Answer 29

contractile cells that wrap around blood vessels; regulate vessel diameter and blood flow

Question 30

astrocytes

Answer 30

end-feet completely surround brain vessels; they can release chemicals that alter BBB permeability within seconds

Question 31

the biochemical elements of the BBB

Answer 31

enzymes and transporters

Question 32

uptake transporters

Answer 32

bring molecules like glucose, lactate and certain amino acids into brain, and allow exchange of ions. e.g. GLUT1 (glucose) and LAT1 (large neutral amino acid transporter)

Question 33

efflux transporters

Answer 33

bind many chemicals that would otherwise be able to penetrate into brain, and pump them back into blood. e.g. P-gp ; can also help clear waste products from brain. e.g. OAT3

Question 34

P-glycoprotein

Answer 34

-most important efflux transporter at the BBB
-can nearly eliminate brain penetration of strong P-gp substrates
-member of ATP-binding cassette (ABC) transporter superfamily
-also expressed in many organs and tissues and often over-expressed in tumors (confers resistance to antineoplastic drugs)
-mediates unidirectional, active transport of many structurally diverse lipid-soluble chemicals and therapeutics from BEC into blood

Question 35

Functions of BBB

Answer 35

-protects brain from exposure to toxic chemicals, infectious agents
-prevents injury from swelling
-somewhat limits ability of brain to sense chemical changes in blood, including endocrine signals
-barrier properties substantially restrict ability to deliver drugs to CNS, making it very difficult to treat CNS diseases

Question 36

BBB disruption in disease

Answer 36

several diseases are associated with damage to the BBB, which can be either a cause or consequence of these diseases (stroke, epilepsy, Alzheimer’s, MS, malaria, diabetes)

Question 37

brain tumors

Answer 37

brain tumors not only physically disrupt the BBB, but they form their own new vasculature, which tends to be leaky

Question 38

Region of CNS not equally protected by BBB

Answer 38

circumventricular organs (CVOs); contain fenestrated capillaries, enabling certain chemo-sensory or secretory functions

Question 39

CVOs with chemosensory functions

Answer 39

enable the brain to respond to changes in blood chemistry (such as area postrema)

Question 40

CVOs with secretory functions

Answer 40

enable a direct pathway for neuro-endocrine communication (such as the pituitary and pineal gland)

Question 41

choroid plexus

Answer 41

-a layer of ependymal cells surrounding a wad of capillaries and connective tissue; found in all ventricles
-produces CSF
-clears waste from brain
-contains tight junctions, transporters, enzymes

Question 42

ependyma

Answer 42

interface between brain tissue and CSF; a single layer of ependymal cells; has incomplete tight junctions that allow some exchange between CSF and nearby brain/spinal cord tissue

Question 43

how come most CNS disorders are not treatable?

Answer 43

BBB excludes hydrophilic drugs, macromolecules, anions, and other compounds; 98% of small-molecule drugs do not cross BBB

Question 44

restrictions for CNS therapeutics/drug development

Answer 44

-low MW
-lipophilic
-cationic non-P-gp substrates

Question 45

drug delivery to the brain

Answer 45

-direct instillation of drug into brain tissue
-direct instillation of drug into CSF
-nasal delivery
-nonselective opening of tight junctions
-selective opening of tight junctions
-inhibition of P-gp
-colloidal carriers
-molecular trojan horse approaches