Drug Metabolism and BBB Flashcards
Drug metabolism
aka “biotransformation”
the process by which enzymes in the body catalyze reactions that change the chemical structure of a drug
principal site of drug metabolism
liver and GI tract
Goal of drug metabolism
to make drugs easier to excrete
Phase 1 enzymes/ reactions of metabolism
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)
Phase II reactions of metabolism
add a large polar group via conjugation reactions to make the drug water-soluble, easier to excrete
Metabolic inactivation
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
Metabolic bioactivation
some drugs are administered as a prodrug which becomes active (or more active) when metabolized. Example: cyclophosphamide
Metabolic toxicity
products of drug metabolism can sometimes be toxic. Example: Tylenol
Cytochrome P450 enzymes
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
UGTs (UDP-glucuronosyltransferase enzymes)
one family of enzymes that catalyzes the largest fraction of Phase II reactions
conjugation reactions
includes methylation, sulfonation, acetylation, glucuonidation; occurs during Phase II metabolism
Enzyme induction
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
Enzyme inhibition
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
How is the exchange of chemicals between blood and CNS regulated?
tightly regulated by specialized endothelial or epithelial cells (termed blood-tissue barriers)
sites with protective blood-tissue barriers
brain, placenta, retina, testis, thymus
paracellular diffusion
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
transcellular lipid diffusion
allows many small lipophilic and gaseous molecules to cross brain endothelial cells into brain (most substances that enter brain enter by this route)
lipid diffusion
operates along a concentration gradient; requires no energy
measure of lipophilicity
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
transport proteins
allow uptake of specific key nutrients and substrates such as amino acids and glucose
transcytosis (receptor-mediated and absorptive)
involve bulk packaging of many types of substrates into vesicles for delivery across the BBB
How do substances move in and out of the blood outside of the CNS?
via capillaries
special CNS capillary structural features that strictly limit entry of fluids/water-soluble compounds into the brain
- tight junctions
- no fenestra (pores)
- few pinocytotic vesicles
- a net negative charge on BEC
- microglia near vessels
- thick basement membrane
- pericytes
- astrocytes
tight junctions
specialized structures form a nearly impenetrable seal between endothelial cells, preventing movement of ions or molecules between endothelial cells
no fenestra (pores)
limits entry of small molecules and proteins
few pinocytotic vesicles
minimizes entry of extracellular fluid, which contains sugars and proteins
a net negative charge on BEC
limits entry of anions into brain
microglia near vessels
restrict pathogen entry into brain
pericytes
contractile cells that wrap around blood vessels; regulate vessel diameter and blood flow
astrocytes
end-feet completely surround brain vessels; they can release chemicals that alter BBB permeability within seconds
the biochemical elements of the BBB
enzymes and transporters
uptake transporters
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)
efflux transporters
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
P-glycoprotein
-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
Functions of BBB
-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
BBB disruption in disease
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)
brain tumors
brain tumors not only physically disrupt the BBB, but they form their own new vasculature, which tends to be leaky
Region of CNS not equally protected by BBB
circumventricular organs (CVOs); contain fenestrated capillaries, enabling certain chemo-sensory or secretory functions
CVOs with chemosensory functions
enable the brain to respond to changes in blood chemistry (such as area postrema)
CVOs with secretory functions
enable a direct pathway for neuro-endocrine communication (such as the pituitary and pineal gland)
choroid plexus
-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
ependyma
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
how come most CNS disorders are not treatable?
BBB excludes hydrophilic drugs, macromolecules, anions, and other compounds; 98% of small-molecule drugs do not cross BBB
restrictions for CNS therapeutics/drug development
-low MW
-lipophilic
-cationic non-P-gp substrates
drug delivery to the brain
-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
