Transporters Flashcards
How does Solute Carriers (SLCs) transport
With concentration gradient or coupled transport
How do ATP Binding Cassette Transporters (ABCs) transport?
Against concentration gradient (ATP-dependent)
Efflux Transporters:
P-glycoprotein
Breast Cancer Resistance Protein
What are the parts of cellular transport
Apical (or luminal) compartment
Basolateral compartment
Paracellular compartment
What transport is Rosuvastatin associated with?
OATP1B1
What does MDR1 do ?
What does inhibiting do?
P-glycoprotein (P-gp)
Drug substrates: Cyclosporine, Digoxin,
Verapamil
-primary function of MDR1 is to pump out a diverse range of compounds from cells, thereby reducing their intracellular concentratio
Inhibiting leads to
-Inc drug absorption
- Inc DDI
-dec efflux
What do BCRP BREAST CANCER
RESISTANCE PROTEIN (ABCG2) do?
What happens when inhibited?
-primary function of BCRP is to efflux a broad range of compounds out of cells, thereby reducing their intracellular concentration
inhibition leads to more drug accumulation, less eflux, and increased suscepitbility to MDR
Mitoxantrone, topotecan,
rosuvastatin, estrogen-sulfate conjugates,
hydrophilic conjugated substrates, urate
Function of OAT1 and OAT3
What does inhibition lead to?
OAT1 and OAT3
* Encoded by SLC22A6 and SLC22A8,
respectively
important in renal secretion (not significant yet
in other tissues)
* Uptake across proximal tubules
(basolateral) for elimination into urine
Drug Substrates: probenecid (gout),
salicylate (inflammation), cidofovir, and
penicillin (antibiotic)
Inhibition leads to decreased renal secretion
Organic Cation Transporter 2 (OCT2)
What does inhibition lead to
important in renal secretion (largely specific
expression in kidney)
* Uptake across proximal tubules
(basolateral) for elimination into urine
cimetidine (antacid), verapamil (hypertension), metformin, (antidiabetic), and cisplatin (anti-cancer)
* Creatinine
OCT2 inhibitors/substrates can elevate serum creatinine
Multidrug and Toxin Extrusion Proteins (MATE1 and
MATE2K)
MATE1 and MATE2K
* Encoded by SLC47A1/2 genes
Efflux from proximal tubules (apical) for
elimination into urine
cimetidine (antacid)
metformin (antidiabetic), and cisplatin (anti-
cancer)
Many are OCT2 substrates; works with OCT2
Decrease in OAT1 OCT2 and MATE1 would lead to
increased AUC and decreased CL
ORGANIC ANION
TRANSPORTING
POLYPEPTIDE
TRANSPORTERS
(SLCO1B1/3)
Important in hepatic clearance (largely specific
expression in hepatocytes)
* Uptake across hepatocytes (basolateral)
for elimination into bile
Digoxin, rifampicin, ACE
inhibitors, taxanes, methotrexate and
statins
Decreased effect can lead top increased myopathic effect
Which statement(s) is/are true for OATP1B1?
A. Subject to clinically significant genetic variability
B. Expressed in the intestine, liver and blood-brain barrier
C. Inhibition can decrease clearance of a drug substrate cleared only by hepatic
metabolism
D. Is present on the sinusoidal (basolateral) membrane of the liver
E. Is a member of the ABC efflux family of transport proteins
F. None of the above
A,C,D
The oral bioavailability of Drug A is 10%. Select all potential reasons for the drug’s poor
bioavailability:
* Drug A is a substrate for P-glycoprotein transport
* Drug A is a substrate for OAT transport
* Drug A undergoes extensive first-pass metabolism
* Drug A undergoes extensive renal elimination
A,C
Activity of which enzyme needs to be considered when prescribing Clopidogrel to a patient?
How does clopidogrel work?
CYP2C19
Inhibits P2RY12 which is responsible for platelet aggregation
