P glycoproteins - Drug interactions

1
P-glycoprotein Interactions

• P. Naina Mohamed
• Pharmacologist

2
Drug transporter proteins

• Transporters or transporter proteins help the
  drugs and endogenous substances to cross
  biological membranes, by carrier-mediated
  processes.
• Types of transporter proteins
• P-glycoprotein (Most well known)
• Bile salt export pump (BSEP or ABCB11) (sister
  P-glycoprotein)
• Other transporters (solute carrier superfamily
  (SLC) of transporters)
• Organic anion transporters (OATs)
• Organic anion-transporting polypeptides (OATPs)
• Organic cation transporters (OCTs)

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P-glycoproteins

• The most well known transporter protein is
  P-glycoprotein.
• The P-glycoprotein (Permeability glycoprotein,
  P-gp or Pgp) is a multidrug transporter.
• It is also known as multidrug resistance protein
  1 (MDR1) or ATP-binding cassette sub-family B
  member 1 (ABCB1).
• P-glycoprotein is a product of the MDR1 gene
  (ABCB1gene) and a member of the ATP-binding
  cassette (ABC) family of efflux transporters.
• P-gp is found more in epithelial and endothelial
  barrier forming tissues such as the gut and
  bloodbrain barrier, and in organs of xenobiotic
  clearance, such as the liver and kidney.

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Functions of P-glycoproteins

• P gp transports various substrates across the
  cell membrane including
• Drugs such as colchicine, tacrolimus and
  quinidine
• Chemotherapeutic agents such as etoposide,
  doxorubicin, and vinblastine
• Cardiac glycosides like digoxin
• Immunosuppressive agents
• Glucocorticoids like dexamethasone
• Lipids, Steroids, Xenobiotics, Peptides and
  Bilirubin
• Regulates the distribution and bioavailability of
  drugs
• Removes toxic metabolites and xenobiotics from
  cells into urine, bile, and the intestinal lumen
• Transports compounds out of the brain across the
  bloodbrain barrier
• Induce Digoxin uptake
• Prevents of ivermectin entry into the central
  nervous system
• Induces the migration of dendritic cells
• Protects the hematopoietic stem cells from
  toxins.

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Mechanism of action of P-glycoprotein

• The functional unit of P gp consists of two
  nucleotide binding domains (NBDs) and two
  trans-membrane domains (TMDs) which are involved
  in the transport of drug substrates. Drug binds
  to TM domain and ATP binds to NBDs.
• Drug binds to a high affinity binding site in the
  TM domain
• Reduces the activiation energy and increases the
  affinity for ATP
• Dimerization of the two NBDs and ATP is tightly
  bound at the interface
• ATP at one of the two NBDs is hydrolyzed
• Conformational change that alters the
  conformation of the drug binding site
• Movement of the drug to a low affinity
  extracellular location
• Release of drug

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P-gp Substrates, Inducers and Inhibitors

• P-gp Substrates
• Digoxin, Loperamide, Quinidine, Vinblastine,
  Talinolol.
• P-gp Inducers
• Avasimibe, Carbamazepine, Phenytoin, Rifampin, St
  Johns wort.
• P-gp Inhibitors
• Amiodarone, Azithromycin, Captopril,
  Cyclosporine, Quinidine, Quinine, Reserpine,
  Ritonavir, Tacrolimus, Valspodar, Verapamil.

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Types of P gp interactions

• P-glycoprotein is an efflux pump found in the
  membranes of certain cells, which can push
  metabolites and drugs out of the cells and affect
  drugs
• Absorption (in the intestine),
• Distribution (to the brain, testis, or placenta)
  and
• Elimination (in the urine and bile) of drugs

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P-glycoprotein (Absorption) interactions

• Induction or inhibition of P-glycoproteins by one
  drug (Inducer or Inhibitor) affect the absorption
  of other drugs (Substrates).
• Drug transporter proteins such as P-glycoprotein,
  determine the oral bioavailability of some drugs
  by ejecting drugs that have diffused across the
  gut lining back into the gut.
• P-glycoprotein in the cells of the gut lining
• Eject some already-absorbed drug molecules back
  into the intestine
• Reduction in the total amount of drug absorbed

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Induction of P-glycoprotein

• Rifampicin (Rifampin)
• Induce P-glycoprotein within the lining cells of
  the gut
• Eject digoxin into gut more vigorously
• Reduced absorption of Digoxin
• Fall in the plasma levels of digoxin

10
Inhibition of P-glycoprotein

• Verapamil
• Inhibit the activity of P-glycoprotein within gut
• Prevents the ejection of Digoxin into the gut
• Increased Digoxin levels

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P-glycoprotein (Distribution) interactions

• Drug transporter proteins such as P-glycoprotein
  limit the distribution of drugs into the brain,
  testes, etc.
• These proteins actively transport drugs out of
  cells when they have passively diffused in.
• P-glycoprotein in the endothelial cells of the
  blood-brain barrier
• Eject certain drugs from the brain
• Reduce CNS penetration
• Decreased CNS effects

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Inhibition of P-glycoprotein

• P-glycoprotein inhibitors increase the uptake of
  drug substrates into the brain, which could
  either increase adverse CNS effects, or be
  beneficial.
• Ketoconazole
• Inhibition of P-glycoprotein
• Prevention of efflux of Ritonavir from CNS
• Increased CSF levels of ritonavir

13
P-glycoprotein (Excretion) interactions

• P-gp plays a key role in the renal elimination of
  certain substrates by means of active secretion
  into the urine.
• P-glycoprotein is expressed on the apical
  (luminal) side of kidney proximal tubule cells
  and may be in other portions of the nephron, such
  as the loop of Henle.
• P-gp may limit reabsorption of substrates that
  are filtered at the glomerulus.
• Induction or Inhibition of P-gp in the kidney may
  lead to drug-drug interactions involving
  alterations in renal clearance.

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Inhibition of P-glycoprotein

• Verapamil, Qunidine or Cyclosporine
• Inhibit the P-glycoprotein-mediated transcellular
  transport of digoxin
• Inhibition of the renal tubular excretion
• Rise in serum digoxin levels
• Increased inotropism and toxic effects

15
Inhibition of P-glycoprotein

• Ketoconazole
• Inhibit the P-glycoprotein transport of
  saquinavir and ritonavir
• Decreased clearance
• Raised serum levels

16
CYP3A4 and P-glycoprotein substrates

• There is an overlap between CYP3A4 and
  P-glycoprotein inhibitors, inducers and
  substrates.
• Therefore, both mechanisms may be involved in
  many of the drug interactions traditionally
  thought to be due to changes in CYP3A4.
• Many drugs that are substrates for CYP3A4 are
  also substrates for P-glycoprotein.
• Digoxin and talinolol are examples of the few
  drugs that are substrates for P-glycoprotein but
  not CYP3A4, and they are therefore useful in
  studying some interactions that may occur by this
  mechanism.
• P-glycoprotein is also expressed in some cancer
  cells (where it was first identified). This has
  led to the development of specific P-glycoprotein
  inhibitors, such as valspodar, with the aim of
  improving the penetration of cytotoxic drugs into
  cancer cells.

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Refrences

• Stockleys Drug Interactions, 9th Edition
• Karen Baxter
• Goodman Gilman's The Pharmacological Basis of
  Therapeutics, 12e Laurence L. Brunton, Bruce A.
  Chabner, Björn C. Knollmann
• Basic Clinical Pharmacology, 12e Bertram G.
  Katzung, Susan B. Masters, Anthony J. Trevor
• Harrison's OnlineFeaturing the complete contents
  of Harrison's Principles ofInternal Medicine,
  18e Dan L. Longo, Anthony S. Fauci, Dennis L.
  Kasper, Stephen L. Hauser, J. Larry Jameson,
  Joseph Loscalzo, Eds
• CURRENT Diagnosis Treatment in Family Medicine,
  3eJeannette E. South-Paul, Samuel C. Matheny,
  Evelyn L. Lewis
• http//www.fda.gov/drugs/developmentapprovalproces
  s/developmentresources/druginteractionslabeling/uc
  m093664.htmPgpTransport
• http//www.ncbi.nlm.nih.gov/pubmed/11804190
• http//www.sciencedirect.com/science/article/pii/S
  0928098705003313