PPT 5 Flashcards
What are the 4 parameters affecting passive diffusion?
Molecular weight
pKa
Lipid solubility
Plasma protein binding
_____ of genes in genome encode for transporter proteins
7%
SLC transporters cross barriers via ______
Primarily passive transport (gradients)
Some active - exchanger and coupled transport
What do SLC proteins transport?
High substrate specificity - nutrients, ions, metabolites, and drugs
What are the 4 types of permeation?
- Aqueous diffusion
- Lipid diffusion
- Endocytosis and exocytosis
- Special carriers
What are special carriers? How do they work?
Membrane drug transporters; molecules bind to drugs and move across barriers
Primary function - transport endogenous substances
What is the main drug efflux transporter?
ATP-binding cassette (ABC) transporters
ABC transporters have ______ substrate specificity
broad
What do drug efflux pumps do?
- Pump drug out of cell
- Cell survival mechanism
What are nucleotide-binding domains?
ATP binds to NBD
What do ABC transporters have in common?
- Transmembrane spanning domains
- Nucleotide-binding domain (NBD)
ABC transporters are _____ specific
location - apical (top) vs basal (bottom)
What are the major drug efflux transporters?
ABC transporters - B, C, G
Which ABC transporter has the broadest substrate specificity?
ABCB1
_______ is critical in the maintenance of BBB
ABCB1
What are the drug interactions with ABCB1?
Drugs that inhibit ABCB1 - Cyclosporine A, Quinidine, Ritonavir
Digoxin is transported by ______
ABCB1
What will happen if a patient is taking digoxin AND a drug that inhibits ABCB1?
Decreased intestinal removal and increased plasma levels (toxicity) of digoxin - arrhythmias
Loperamide is transported by ______
ABCB1
How does loperamide work as an antidiarrheal?
Although loperamide is an opioid, since it is transferred by ABCB1 in the gut, it stays in the gut – antidiarrheal
- No CNS effects: GI ABCB1
How do people abuse loperamide?
- When given with quinidine (ABCB1 inhibitor)
- Systemic absorption
- CNS effects (respiratory suppression)
ABCC primarily transports _______
antineoplastic drugs
ABCG transports ______
- Breast cancer resistance protein (BCRP)
- Antineoplastics, toxins, food-borne carcinogens
- Folate transport
The majority of drugs are absorbed through these barriers in ABC transporters
Intestines, liver, kidneys
The majority of the drugs are pumped back out of these barriers via ABC transporters
Placenta, BBB, blood-CSF barrier
_______, _______, and _______ prevent drugs from crossing the BBB
ABC transporters
The vascular epithelium
Other cells - astrocytes and podocytes - regulate how much drug reaches neurons
ABC transporters in the GI tract are primarily on the ______ surface
apical - microvilli (increase surface area)
Most of the ABC transporters are in the _____
gut and liver
Gut - most common – ABCG2 (BCRP), but has all types
________ transport out glucuronides from hepatic metabolism back into the intestine
ABCC (MRPs)
The liver facilitates xenobiotic metabolism, excretion into____
bile
Types of transporters in the liver
SLC type (OATPs), ABCs (all)
Lipophilic drugs can cross ____
barriers - BBB, placenta
nicotine, alcohol
Transporter protein expression is upregulated by:
PXR, steroids, xenobiotics
Transporter protein expression is downregulated by:
- Endothelin
- Partial agonist - antagonist function
xenobiotics
chemical substances that are foreign to the biological system (made outside the body)
Regulation of cholesterol in the cell is accomplished by ______
ABCA1 transporter
Blood CSF barrier is not as ______ as the BBB
selective
How is Tylenol metabolized when taken orally?
From intestine taken into the bloodstream where it undergoes first-pass effect in the liver. Tylenol metabolism is a phase II reaction of glucuronidation (a glucose molecule is attached to the Tylenol) it is now a non-toxic glucuronide. This is put into the bile that then returns to the intestine. It is now recognized by the ABC transporters because of the glucuronidation, it is transported to the intestine where it can be excreted via defecation.
Drug transporter direction “flux” is determined by
Their location and what the function of the organ they are located on is
The BBB is composed of _____
tight junctions
Molecules that can cross the BBB include
Small, lipophilic molecules (O2, CO2, ehtanol, nicotine) - transcellular lipophilic pathway
Medium molecules (glucose, amino acids, nucleotides) - carrier protein-mediated pathway
Large molecules (insulin, IgG, albumin, histone) - endocytosis
