Drug Transport - Pelis 1 Flashcards Preview

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Flashcards in Drug Transport - Pelis 1 Deck (29)
1

ADME

Drug absorption, distribution, metabolism and excretion
Influenced by drug transporters and metabolizing enzymes

2

Class 1 Drugs

High solubility, high permeability
Metabolism

3

Class 2 Drugs

Low solubility, high permeability
Metabolism

4

Class 3 Drugs

High solubility, low permeability
Renal or bile excretion
Need transporters

5

Class 4 Drugs

Low solubility, low permeability
Renal or bile excretion
Need transporters

6

ATP binding cassette

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

7

Solute carrier family

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

8

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

9

Substrates of transporters

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

10

Efflux transporters

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

11

Uptake transporters

OCTs, OATs, organic anion transporting polypeptides

12

P-glycoprotein

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

13

Multidrug resistance association proteins

Organic anions
Efflux transporter

14

Breast cancer resistance protein

BCRP
Efflux transporter
Neutral and organic anions

15

Multidrug and toxin extruder

MATE1
Efflux transporter
Organic cations

16

OCT

Uptake transporter
Organic cations

17

OAT

Uptake transporter
Organic anion

18

Organic anion transporting polypeptide

OATP
Uptake transporter
Organic anions

19

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

20

Digoxin

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

21

Acylcovir

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

22

OATP1B1

Reduced P1B1, statins build up and could cause myopathy

23

Cisplatin

Easily transported into kidneys and can kill the kidney

24

Probenecid

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

25

2 questions of drug development

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

26

In vitro tools in drug development

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)

27

Why not use animal models?

Differences in transporters

28

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

29

Physiological-based pharmacokinetic modeling

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