16.1. A person swallows aspirin tablets to attempt to relieve muscle soreness. In order for the aspirin to take effect, it must
A. Bind to P-gp to stimulate MDR.
B. Cross intestinal epithelial cells to enter the circulation.
C. Stimulate ATP hydrolysis of an ABC transporter.
D. Undergo antiport from the stomach.
E. Use an ABC transporter to enter the liver.
16.1: Correct answer = B. Drugs taken by the oral route have to cross the barrier of epithelial cell membranes in the intestine in order to enter the circulation. P-gp is an ABC transporter involved in MDR. It transports drugs out of cells and would not aid in the absorption of aspirin. ABC transporters transport drugs out of cells and not into them. Antiport from the stomach would not enable the drug to enter into the circulation since it must still cross the barrier of intestinal epithelial cells in order to enter the circulation.
16.2. A new protein drug is being developed with the goal of treating Huntington’s disease, a neurodegenerative disorder. The main obstacle to delivery of this drug to the central nervous system will most likely be
A. Absorption by the gastrointestinal tract.
B. Endothelial cells lining blood vessels within the central nervous system.
C. Lack of an ABC transporter to deliver the drug to appropriate cells.
D. MDR developing quickly.
E. Poor solubility in aqueous solutions of the body.
16.2: Correct answer = B. The main barrier to delivery of drugs to the central nervous system is the blood-brain barrier. Endothelial cells lining the blood vessels within the central nervous system form this barrier that excludes most of the large molecules (>400 daltons) from entering. Absorption by the gastrointestinal tract may occur, but if the drug cannot access the central nervous system owing to the blood-brain barrier, then effects will not be observed. ABC transporters transport drugs out of cells. Lack of expression of an ABC transporter could improve the delivery of the drug across the blood-brain barrier. MDR develops in response to actions of ABC transporters, particularly P-gp. Solubility in aqueous solutions could be very high but if the drug cannot cross the blood-brain barrier, it will not gain access to the central nervous system to treat the disorder.
16.3. A 24-year-old female is given a ?-lactam antibiotic to treat a bacterial infection. This drug will most likely cross intestinal epithelial cells to gain access to the circulation by
A. ABC transporter–mediated transport.
B. Binding to P-gp on the surface of epithelial cells.
C. Inhibiting ATP hydrolysis of an ABC transporter.
D. Passively diffusing through intestinal epithelial cells.
E. PEPT transporter–mediated passage.
16.3: Correct answer = E. ?-lactam antibiotics are transported by PEPT transporters. ABC transporters transport drugs out of cells, not into them. Inhibition of ATP hydrolysis of an ATP transporter would not affect entry of a ?-lactam antibiotic into intestinal epithelial cells. P-gp is an ABC transporter. Passive diffusion is no longer believed to be an important route of drug entry into cells.
16.4. A 38-year-old male has been taking St John’s wort for 2 years. He obtains this herbal preparation over the internet and has never mentioned his use of St John’s wort to his physician. He develops atrial fibrillation (abnormal heart rhythm) and is prescribed digoxin. Therapy with digoxin is ineffective. These findings are best explained by
A. Competition of St John’s wort and digoxin for the same SLC transporter.
B. MDR developing from St John’ wort and digoxin.
C. Poor solubility of digoxin in the plasma membrane of intestinal epithelial cells.
D. St John’s wort having greater affinity for a transporter than digoxin.
E. St John’s wort upregulation of P-gp which interferes with digoxin absorption.
16.4: Correct answer = E. St John’s wort upregulates P-gp, an ABC transporter. Overexpression of P-gp prevents the absorption of some other drugs, including digoxin, because P-gp exports the drug out of the cell. St John’s wort and digoxin do not compete for binding to the same receptor and receptor affinity would not be an important factor. Digoxin is normally transported across intestinal epithelial cells (when P-gp is not overexpressed) and its solubility in the membrane is not a consideration since a transporter is normally used.
16.5. A patient’s cancer cells develop MDR to chemotherapy agents. Expression of which of the following proteins may be expected on the cancer cells?
16.5: Correct answer = C. ABCB1 is the ABC transporter involved in MDR. It exports drugs from cells rendering the cells resistant to the effects of the drugs. SLCs are solute-linked carriers that transport many drugs into cells. OAT, OATB1P, and PEPT are examples of SLCs.