Drug Transporters

• Drug transporters move drugs across cell membranes.
• There are two main types with the net effect of maintaining a concentration gradient across the cell membrane:
  • Efflux transporters - remove lipophilic drugs out of cells and out of the body.
  • Ion transporters (anion and cation) - move hydrophilic drugs in and out of cells and the body.
• Genetic polymorphism exists.
• Drugs can be substrates of more than one transporter.
• The following lists are not exhaustive and our knowledge of drug transporter is less than our knowledge of CYP450 metabolism.

Efflux Transporters

P-glycoprotein

• The most important efflux transporter to drug disposition is P-glycoprotein (Pgp)
• Found in gut mucosa, biliary tract, hepatocytes, proximal renal tubules and at the blood/brain barrier. (Also found in some tumour cells).
• Reduces gastrointestinal absorption of drugs; reduces drug uptake into the CNS; and facilitates renal and biliary excretion.
• P-glycoprotein substrates are often also CYP3A substrates.
• This list is not exhaustive.

Substrates

Main drug classes predominantly transported by Pgp include:

• cytotoxics, immunosuppressants, HIV inhibitors

Main Drugs

• commonly used drugs

  carvedilol	digoxin	loperamide	rifampicin
  celiprolol	diltiazem	morphine	roxithromycin
  colchicine	erythromycin	nifedipine	simvastatin
  dabigatran etexilate	fexofenadine	progesterone

• cytotoxics, immunosuppressants, HIV protease inhibitors

  ciclosporin	etoposide	nelfinavir	vinblastine
  daunorubicin	indinavir	paclitaxel	vincristine
  docetaxel	mitomycin C	saquinavir
  doxorubicin	mitoxantrone	tacrolimus

Inhibitors (usually lead to increased systemic concentrations)

Inducers (usually lead to decreased systemic concentrations)

Ion Transporters (Solute Transporters)

• Can be subdivided into:
  • Anion (organic anion transporters – OATs)
  • Amphiphilic - Both lipophilic and hydrophilic (organic anion transporter polypeptides – OATPs) transporters
  • Cation (organic anion transporters – OCTs)
    • Note: Each group has several different transporters.
• Facilitate polar/ionic drugs entering cells and crossing "barriers":
  • Gut
  • Biliary tree
  • Blood/brain barrier
  • Renal tubules
• Are found on all cells and differ between tissues.

Organic Anion Transporters (OATs)

• Transport organic anions including bilirubin.

Substrates

Main drug classes predominantly transported by OATs include:

• Betalactam antibiotics

Main Drugs

Inhibitors (usually lead to increased systemic concentration)

Organic Anion-Transporting Polypeptides (OATPs)

• Transport amphiphilic organic compounds including some hormones.

Substrates

Main drug classes predominantly transported by OATPs include:

• statins

Main Drugs

Inhibitors (usually lead to increased systemic concentrations)

Organic Cation Transporters (OCTs)

• Transport organic cations.

Substrates

Main drug classes predominantly transported by OCTs include:

• Alpha blockers

Main Drugs

Inhibitors (usually lead to increased systemic concentrations)

Topic Code: 93361

must be prescribed or recommended by a consultant.