Ex. 2 L6: Drug Transporters

Question 1

Types of drug transport

Answer 1

Paracellular passive diffusion
Transcellular passive diffusion
Uptake transport
Endo/exocytosis
Efflux transport

Question 2

Uptake and Efflux transport use

Answer 2

Carriers - matter of direction; transport take drugs in, efflux moves drugs out

Question 3

Role of drug transporters in drug disposition

Answer 3

Substrate of one of the transporters
Several minutes after iv infusion
-A lot of drug present in liver
-A lot of drug starts in kidney because after it is metabolized it is excreted into the urine
Brain - do not see as much of the drug
Brain has endothelial cells w/transporters that pump drug out of the brain
-a lot of drug unable to reach brain

A lot of drugs metabolized in intestine - excreted into bile by action of P-glycoprotein
Find drug in feces
-

Question 4

Efflux transporter

Answer 4

P-gp (P-glycoprotein)

Question 4

Uptake Transporters

Answer 4

OATP (organic anion transporting protein)
PEPT1 (peptide transporter

Question 5

Major drug transporters expressed in intestinal epithelia:

Answer 5

OATP
PEPTI
P-gp

Question 6

Major drug transporters expressed in Hepatocytes

Answer 6

OATP
P-gp

Question 7

Major drug transporters expressed in kidney proximal tubules

Answer 7

P-gp

Question 8

Major drug transporters expressed in blood-brain barrier

Answer 8

P-gp

Question 9

P-glycoprotein (P-gp)

Answer 9

Efflux transporter affecting permeability of drugs
Expression of P-glycoprotein leads to resistance to certain drugs
Also called MDR1 (multi-drug resistance I)
P-gp pumps drugs in the direction of eliminating them from the bodies

Expression of Pgp on cancer cells leads to resistance of many drugs - pumps them out - decreased internal cell count

Expressed on:
Brain
Liver
Kidney
Small intestine
Testis

Question 10

P-gp tissue distribution

Answer 10

Expressed on the apical side
Transport drugs out of bodies or organs

Intestine - eliminates out of intestine

Hepatocyte - promotes elimination of drug into bile

BBB - pumps out of brain; protects brain

Kidney: Pump blood out of body and into urine

Pgp protects body from potentially toxic/harmful substances

Question 11

Blood Brain Barrier (BBB)

Answer 11

Capillaries stick together
-Drugs can only cross endothelial cells through diffusion, or carrier mediated transport
-Drugs stick together through tight junction

Question 12

P-glycoprotein in brain:

Answer 12

Body came up with efflux system to pump toxic molecule out of brain
-Expressed on apical membrane
Helpful drugs can go through membrane/capillaries by endo/exocytosis
Can cut through membrane using active transport system

Question 13

Pgp substrates

Answer 13

Substrates vary greatly in their structure and functionality, ranging from small molecules such as organic cations, carbohydrates, amino acids, and some antibiotics to macromolecules such as polysaccharides

Question 14

Pgp substrates: Anticancer agents

Answer 14

Paclitaxel
Topotecan
Etoposide

Question 15

Pgp substrates: Anti-HIV agents

Answer 15

Indinavir
Ritonavir
Saquinavir

Question 16

Pgp substrates: Immunosuppressants

Answer 16

Cyclosporine A
Tacroliums

Question 17

Pgp substrates: Lipid-lowering agents

Answer 17

Lovastatin
Atorvastatin

Question 18

Pgp substrates: Opiods

Answer 18

Loperamide

Question 19

Pgp inhibitors:

Answer 19

Most of the inhibitors are also substrates for P-gp and are capable of competitively inhibiting P-gp function

Question 20

Pgp inhibitors: Anti-HV agents

Answer 20

Lopinavir
Ritonavir
Saquinavir
Telaprevir
Tipranavir

Question 21

Pgp inhibitors: Anti-infectives

Answer 21

Clarithromycin
Itraconazole

Question 22

Pgp Inhibitors: Cardiovascular

Answer 22

Amiodarone
Carvedilol
Quinidine
Propafenone
Verapamil

Question 23

Drug-Drug interaction via P-gp:

Answer 23

Monkey study radiolabeled N-desmethyl loperamide
loperamide: Peripherally acting opioid receptor agonist

Does not reach the brain because pgp is there to pump drug out of brain

When loperamide is present - Distribution in brain tissue

Question 24

PGP in the liver

Answer 24

Hepatocytes - also major organs for bile production Bile - bile hepatocyte - bile canaliculus Bile eventually reaches small intestine Hepatocytes get drug source from blood stream - drugs deliver through blood flow and reach hepatocytes Portion of drug can be metabolized - metabolized portion can be excreted into the bile canaliculus PGP (MDR1) is expressed on the **bile canaliculus membrane of hepatocyte** Drugs reaching hepatocyte can be pumped into bile either as **parent drug or metabolites**

Question 25

Inhibition of p-gp in liver leads to

Answer 25

Decreased drug concentration

Question 26

P-gp in placenta

Answer 26

**Pgp on apical membrane** Pumps drug out of blood - fetal tissue Becomes part of system - there to pump **blood out of fetal tissue to protect fetus**

Question 27

Pgp in placenta: inhibition leads to...

Answer 27

**increased** drug transfer **across placenta**

Question 28

OATP (Organic anion transporting protein) superfamily

Answer 28

>300 members with at least 11 OATPs expressed in human Uptake transporters

Question 29

OATP substrates:

Answer 29

Endogenous compounds: bilirubin, bile salts, steroid hormone metabolites (e.g. estradiol glucuronide) Xenobiotics: fexofenadine, statins

Question 30

Statins:

Answer 30

Inhibitors of 3-hydroxy-methyglutaryl coenzyme A (HMG-CoA) reductase in the liver Cornerstone of lipid-lowering therapy to reduce the risk of coronary heart disease **Most statins are substrate of OATP1B1**

Question 31

Statins and OATP1B1

Answer 31

Life-threatening side effect: **rhabdomyolysis** Cerivastatin withdrawn in 2001 due to **increased risk of myopathy associated with higher doses and drug interactions** -During postmarketing surveillance, 52 deaths were reported, mainly from rhabdomyolysis and its resultant renal failure Risks were higher in patients using fibrates, mainly gemfibrozilm and in patients using the highest (0.8mg/day) dose of cerivastatin

Question 32

What are expected outcomes when OATP1B1 is inhibited?

Answer 32

Decrease amount of statin reaching hepatocytes (target) Lower efficacy (due to decreased uptake by the target organ) **increase** statin plasma concentration (increased side effects (e.g. myopathy)

Question 33

Drug-Drug interaction via OATP1B1

Answer 33

Gemfibrozil -Lipid lowering agent -OATP1B1 inhibitor Gemfibrozil **increases the incidence of statin-induced myopathy** Commonly combined with statin **Much greater statin exposure in presence of Gemfibrozil** **increased exposure of statin can lead to statin induced myopathy**

Question 34

OATP1B1 genetic polymorphisms

Answer 34

OATP1B1 is inhibited

Question 35

Intestinal drug transporters

Answer 35

**PEPTI** On intestine Pumps drug into hepatocytes helping during drug absorption **OATP** Also works as **uptake** transporter Both work to **pump drug into cell**

Question 36

Drug-Drug interaction via OATP

Answer 36

Fexofenadine Fexofenadine is an OATP1A2 and OATP2B1 substrate Grapefruit juice (GFJ) **inhibits OATP** OATP - combined w/grapefruit juice inhibits OATP -much **decreased drug exposure and absorption**

Question 37

PEPT1 (Peptide transporter 1)

Answer 37

A peptide transporter in the small intestine Uptake transporter Substrates -Dipeptides and tripeptides B-lactam antibiotics PepT1 can be utilized to improve oral absorption of drugs **Valacyclovir** -Significantly improve oral absorption because this becomes a substrate of PepT1

Question 38

PEPT1: Valacyclovir

Answer 38

When administered at the same dose, valacyclovir leads to **higher systemic exposure** to acyclovir Low exposure happens because acyclovir is not readily absorbed ^Same dose of valacyclovir: -Better intestinal absorption Leads to higher systemic exposure