Drug Transport - Pelis 1

Question 1

ADME

Answer 1

Drug absorption, distribution, metabolism and excretion

Influenced by drug transporters and metabolizing enzymes

Question 2

Class 1 Drugs

Answer 2

High solubility, high permeability

Metabolism

Question 3

Class 2 Drugs

Answer 3

Low solubility, high permeability

Metabolism

Question 4

Class 3 Drugs

Answer 4

High solubility, low permeability
Renal or bile excretion
Need transporters

Question 5

Class 4 Drugs

Answer 5

Low solubility, low permeability
Renal or bile excretion
Need transporters

Question 6

ATP binding cassette

Answer 6

ABC

Hydrolyze ATP to pump drugs out of cells (efflux pumps)

Question 7

Solute carrier family

Answer 7

SLC
Energy in solute gradient, ie. Na, to move drugs in or out of cells
Uptake or efflux

Question 8

Epithelial transport

Answer 8

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

Question 9

Substrates of transporters

Answer 9

Low MW
Neutral, organic cations/anions, zwitterions
Endogenous compounds
Xenobiotics

Question 10

Efflux transporters

Answer 10

P-glygoprotein
Multidrug resistance association proteins
Breast cancer resistance protein
Multidrug and toxin extruder

Question 11

Uptake transporters

Answer 11

OCTs, OATs, organic anion transporting polypeptides

Question 12

P-glycoprotein

Answer 12

Pgp
Efflux transporter
Neutral, organic ions
First drug transporter identified
~50% of marketed on drugs are substrates
Absent from CSF

Question 13

Multidrug resistance association proteins

Answer 13

Organic anions

Efflux transporter

Question 14

Breast cancer resistance protein

Answer 14

BCRP
Efflux transporter
Neutral and organic anions

Question 15

Multidrug and toxin extruder

Answer 15

MATE1
Efflux transporter
Organic cations

Question 16

OCT

Answer 16

Uptake transporter

Organic cations

Question 17

OAT

Answer 17

Uptake transporter

Organic anion

Question 18

Organic anion transporting polypeptide

Answer 18

OATP
Uptake transporter
Organic anions

Question 19

Transporter effects on oral bioavailability

Answer 19

Can either increase or decrease, some transporters can be highjacked to increase oral bioavailability
Efflux pumps like Pgp reduce oral bioavailability

Question 20

Digoxin

Answer 20

Cardiac glycoside used for atrial fibrillation and heart failure
Low therapeutic index
Pgp reduces bioavailability
Absorption increases with Pgp inhibition

Question 21

Acylcovir

Answer 21

Low bioavailability
Antiviral drug
Valacyclovir (prodrug) is a substrate of PEPT1 and is readily absorbed

Question 22

OATP1B1

Answer 22

Reduced P1B1, statins build up and could cause myopathy

Question 23

Cisplatin

Answer 23

Easily transported into kidneys and can kill the kidney

Question 24

Probenecid

Answer 24

Slows down renal penicillin transport
Allows lower doses of penicillin
Take with cidofovir to prevent nephrotoxicity

Question 25

2 questions of drug development

Answer 25

1. Does out new chemical entity inhibit other transporters and enzymes?
2. What transporters and enzymes are involved in ADME of our NCE

Question 26

In vitro tools in drug development

Answer 26

1. Nonpolarized cells (human embryonic kidney cells, Chinese hamster ovary cells, Xenopus oocytes)
2. Polarized cells (Madin Darby Canine Kindey, Porcine kidney cell line)
3. Inside-out membrane vesicles (efflux transporters)
4. Caco-2 (intestine or BBB model)
5. Primary hepatocytes (liver model)

Question 27

Why not use animal models?

Answer 27

Differences in transporters

Question 28

Caco2 assay

Answer 28

Efflux transporter phenotyping and passive permeability assessment
Routine assay, first done in drug development
Observe net flux ratio and inhibition by Pgp inhibitors

Question 29

Physiological-based pharmacokinetic modeling

Answer 29

Used to predict drug exposure and response in virtual human populations using in vitro data