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Kinetics > Ex. 2 L6: Drug Transporters > Flashcards

Ex. 2 L6: Drug Transporters Flashcards

1
Q

Types of drug transport

A

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

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2
Q

Uptake and Efflux transport use

A

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

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3
Q

Role of drug transporters in drug disposition

A

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
-

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4
Q

Efflux transporter

A

P-gp (P-glycoprotein)

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4
Q

Uptake Transporters

A

OATP (organic anion transporting protein)
PEPT1 (peptide transporter

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5
Q

Major drug transporters expressed in intestinal epithelia:

A

OATP
PEPTI
P-gp

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6
Q

Major drug transporters expressed in Hepatocytes

A

OATP
P-gp

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7
Q

Major drug transporters expressed in kidney proximal tubules

A

P-gp

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8
Q

Major drug transporters expressed in blood-brain barrier

A

P-gp

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9
Q

P-glycoprotein (P-gp)

A

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

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10
Q

P-gp tissue distribution

A

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

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11
Q

Blood Brain Barrier (BBB)

A

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

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12
Q

P-glycoprotein in brain:

A

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

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13
Q

Pgp substrates

A

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

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14
Q

Pgp substrates: Anticancer agents

A

Paclitaxel
Topotecan
Etoposide

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15
Q

Pgp substrates: Anti-HIV agents

A

Indinavir
Ritonavir
Saquinavir

16
Q

Pgp substrates: Immunosuppressants

A

Cyclosporine A
Tacroliums

17
Q

Pgp substrates: Lipid-lowering agents

A

Lovastatin
Atorvastatin

18
Q

Pgp substrates: Opiods

A

Loperamide

19
Q

Pgp inhibitors:

A

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

20
Q

Pgp inhibitors: Anti-HV agents

A

Lopinavir
Ritonavir
Saquinavir
Telaprevir
Tipranavir

21
Q

Pgp inhibitors: Anti-infectives

A

Clarithromycin
Itraconazole

22
Q

Pgp Inhibitors: Cardiovascular

A

Amiodarone
Carvedilol
Quinidine
Propafenone
Verapamil

23
Q

Drug-Drug interaction via P-gp:

A

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

24
Q

PGP in the liver

A

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

25
Q

Inhibition of p-gp in liver leads to

A

Decreased drug concentration

26
Q

P-gp in placenta

A

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

27
Q

Pgp in placenta: inhibition leads to…

A

increased drug transfer across placenta

28
Q

OATP (Organic anion transporting protein) superfamily

A

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

29
Q

OATP substrates:

A

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

30
Q

Statins:

A

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

31
Q

Statins and OATP1B1

A

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

32
Q

What are expected outcomes when OATP1B1 is inhibited?

A

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)

33
Q

Drug-Drug interaction via OATP1B1

A

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

34
Q

OATP1B1 genetic polymorphisms

A

OATP1B1 is inhibited

35
Q

Intestinal drug transporters

A

PEPTI
On intestine
Pumps drug into hepatocytes helping during drug absorption

OATP
Also works as uptake transporter

Both work to pump drug into cell

36
Q

Drug-Drug interaction via OATP

A

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

37
Q

PEPT1 (Peptide transporter 1)

A

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

38
Q

PEPT1: Valacyclovir

A

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

Kinetics (20 decks)

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