Drug Transport - Pelis 1 Flashcards
ADME
Drug absorption, distribution, metabolism and excretion
Influenced by drug transporters and metabolizing enzymes
Class 1 Drugs
High solubility, high permeability
Metabolism
Class 2 Drugs
Low solubility, high permeability
Metabolism
Class 3 Drugs
High solubility, low permeability
Renal or bile excretion
Need transporters
Class 4 Drugs
Low solubility, low permeability
Renal or bile excretion
Need transporters
ATP binding cassette
ABC
Hydrolyze ATP to pump drugs out of cells (efflux pumps)
Solute carrier family
SLC
Energy in solute gradient, ie. Na, to move drugs in or out of cells
Uptake or efflux
Epithelial transport
Drug transporters facilitate transport of therapeutic drugs and more across epithelia
Transporters considered important for pharmacokinetics and their predominant direction of transport
Biliary, renal secretion
Substrates of transporters
Low MW
Neutral, organic cations/anions, zwitterions
Endogenous compounds
Xenobiotics
Efflux transporters
P-glygoprotein
Multidrug resistance association proteins
Breast cancer resistance protein
Multidrug and toxin extruder
Uptake transporters
OCTs, OATs, organic anion transporting polypeptides
P-glycoprotein
Pgp Efflux transporter Neutral, organic ions First drug transporter identified ~50% of marketed on drugs are substrates Absent from CSF
Multidrug resistance association proteins
Organic anions
Efflux transporter
Breast cancer resistance protein
BCRP
Efflux transporter
Neutral and organic anions
Multidrug and toxin extruder
MATE1
Efflux transporter
Organic cations
OCT
Uptake transporter
Organic cations
OAT
Uptake transporter
Organic anion
Organic anion transporting polypeptide
OATP
Uptake transporter
Organic anions
Transporter effects on oral bioavailability
Can either increase or decrease, some transporters can be highjacked to increase oral bioavailability
Efflux pumps like Pgp reduce oral bioavailability
Digoxin
Cardiac glycoside used for atrial fibrillation and heart failure
Low therapeutic index
Pgp reduces bioavailability
Absorption increases with Pgp inhibition
Acylcovir
Low bioavailability
Antiviral drug
Valacyclovir (prodrug) is a substrate of PEPT1 and is readily absorbed
OATP1B1
Reduced P1B1, statins build up and could cause myopathy
Cisplatin
Easily transported into kidneys and can kill the kidney
Probenecid
Slows down renal penicillin transport
Allows lower doses of penicillin
Take with cidofovir to prevent nephrotoxicity
2 questions of drug development
- Does out new chemical entity inhibit other transporters and enzymes?
- What transporters and enzymes are involved in ADME of our NCE
In vitro tools in drug development
- Nonpolarized cells (human embryonic kidney cells, Chinese hamster ovary cells, Xenopus oocytes)
- Polarized cells (Madin Darby Canine Kindey, Porcine kidney cell line)
- Inside-out membrane vesicles (efflux transporters)
- Caco-2 (intestine or BBB model)
- Primary hepatocytes (liver model)
Why not use animal models?
Differences in transporters
Caco2 assay
Efflux transporter phenotyping and passive permeability assessment
Routine assay, first done in drug development
Observe net flux ratio and inhibition by Pgp inhibitors
Physiological-based pharmacokinetic modeling
Used to predict drug exposure and response in virtual human populations using in vitro data
